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Thermodynamic, Computational Solubility Parameters in Organic Solvents and In Silico GastroPlus Based Prediction of Ketoconazole
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Thermodynamic, Computational Solubility Parameters in Organic Solvents and In Silico GastroPlus Based Prediction of Ketoconazole
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  • Sultan Alshehri*
    Sultan Alshehri
    Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
    *Email:[email protected]. Mobile: +966114678042.
    More by Sultan Alshehri
    Orcidhttp://orcid.org/0000-0002-0922-9819
  • Afzal Hussain*
    Afzal Hussain
    Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
    *Email: [email protected]; [email protected]. Mobile: 0564591584.
    More by Afzal Hussain
    Orcidhttp://orcid.org/0000-0002-6275-5375
  • Mohd Neyaz Ahsan
    Mohd Neyaz Ahsan
    Department of Medical Laboratory Technology University Polytechnic, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
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  • Raisuddin Ali
    Raisuddin Ali
    Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
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  • Mohd Usman Mohd Siddique
    Mohd Usman Mohd Siddique
    Department of Pharmaceutical Chemistry, Shri Vile Parley Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharastra, India
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ACS Omega

Cite this: ACS Omega 2021, 6, 7, 5033–5045
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https://doi.org/10.1021/acsomega.0c06234
Published February 11, 2021

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Abstract

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The study aimed to select a suitable solvent capable to solubilize ketoconazole (KETO) and serve as a permeation enhancer across the skin. Experimental solubility and Hansen solubility parameters were obtained in ethanol, dimethyl sulfoxide (DMSO), ethylene glycol, oleic acid, span 80, limonene, eugenol, transcutol (THP), labrasol, and propylene glycol. Thermodynamic functional parameters and computational models (vanʼt Hoff and Apelblat) validated the determined solubility in various solvents at T = 298.2 K to 318.2 K and P = 0.1 MPa. The HSPiP software estimated the solubility parameters in the solvents. The maximum mole fractional solubility values of KETO were found to be in an order as oleic acid (8.5 × 10–3) > limonene (7.3 × 10–3) > span 80 (6.9 × 10–2) > THP (4.9 × 10–2) > eugenol (4.5 × 10–3) at T = 318.2 K. The results of the apparent thermodynamic analysis confirmed that the dissolution rate was endothermic and entropy driven. The GastroPlus program predicted significantly high permeation of KETO (79.1%) in human skin from the KETO-THP construct as compared to drug solution (38%) and excellent immediate release from THP-solubilized construct (90% < 1 h). Hence, THP could be a better option for topical, transdermal, and oral formulation.

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Introduction

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The incidence of fungal infections occurred about 40 million in developing and under developing nations as per global estimates. (1) Chemically, ketoconazole (KETO) is an azole type (±) (cis-1-acetyl-4-[4-[2-(2,4-dichlorophenyl-2-(1H-imidazol-1ylmethyl)-1,3-dioxalon-4-yl]methoxy]phenyl]piperazine) antifungal drug for local and systemic treatments. (2) The empirical molecular formula and molecular weight of KETO are C26H28Cl2N4O4 (Figure 1A) and 531.43 g mol–1, respectively. (3) Azole molecules are the first choice option to treat cutaneous and systemic fungal infections. However, the drug possesses poor aqueous solubility (0.04 mg/mL at 25 °C), high partition coefficient (logP = 4.31), and limited oral bioavailability. (3) The drug is reported to treat several cutaneous fungal infections such as (a) onychomychosis (nail fungal infection), (b) psoriasis, (c) dermatitis, and (d) fungal infections (Candida species and Cryptococcus neoformans) associated with other diseases (human immunodeficiency virus). (4) The poor aqueous solubility challenged the drug for parenteral, oral, and topical delivery to treat these fungal infections. A high oral dose owing to limited aqueous solubility results in dose-related toxic side effects. Therefore, topical and transdermal delivery could be a suitable alternative using a suitable permeation enhancer. Hossin et al. investigated the nail–drug interaction (affinity) using Hansen solubility parameters, which can assist formulation scientists to design a suitable carrier or solvent selection (DMSO, N-methyl pyrrolidone, ethanol, and ethylene glycol) for topical application with improved efficacy. (5) Hashemzadeh and Jouyban studied the binary system of ethanol + water mixture for improved solubility of KETO at various temperatures using a Jouyban–Acree model of co-solvency. (2) Moreover, authors reported that KETO exhibited the maximum mole fractional solubility (0.117) at 308.2 K when the mass fraction of ethanol in water was 0.8. (2) They also reported KETO molar solubilities of 1.40 × 10–5 and 2.90 × 10–5 at 293.2 and 308.2 K in water, respectively. (2) Jouyban et al. explored the solubility of KETO in various polyethylene glycol-200 + water binary systems at various temperature range (298.2–318.32 K) wherein the computational models (Jouyban–Acree and vanʼt Hoff models) were the best fit to the experimental solubility data within acceptable range of mean relative deviation (MRD) values. (6) In further development, polyethylene glycols (of various molecular weights such as 200, 400, and 600) were used for the solubility study of KETO as binary as well as ternary with ethanol or water at 298.2 K. Soltanpour and Nazemi investigated that the binary mixture of ethanol + water showed relatively less molar solubility (0.041–3.071) over explored mass fractions (0.1–0.9), whereas the binary mixture of the PEG + water system exhibited higher molar solubility (0.065–3.86 for PEG200, 0.04–9.87 for PEG400, and 0.145–10.71 for PEG600) at the same mass fraction and experimental temperature (298.2 K). (7) They also studied that the binary system of ethanol + PEG revealed increased solubility with increase in the PEG molecular weight (PEG600 > PEG400 > PEG200). (7) Considering these, there are several safe and biocompatible permeation enhancers, which may be explored for solubilizing KETO, which can assist enhanced permeation across the stratum corneum (SC) after topical or transdermal application. These are ethanol, propylene glycol, labrasol, transcutol, eugenol, limonene, span 80, oleic acid, ethylene glycol, and DMSO (dimethyl sulfoxide). (8) KETO (bearing two pKa values such as 2.94 and 6.51) solubility in acetate buffer (pH = 5.0) was reported to be 0.3 mg/mL, and the solubility was increased to 4.6 mg/mL by fabricating as KETO succinate co-crystals. KETO is a weakly basic molecule. (9)

Figure 1

Figure 1. (A) Chemical structure of ketoconazole, (B) DSC thermogram of pure and equilibrated ketoconazole (recovered from methanol), and (C) chromatogram of pure ketoconazole with a retention time of 6.789 min from method validation (Empower 2 software)

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No studies have been conducted for Hansen solubility, thermodynamic parameters, computational validation, and the GastroPlus-based in silico prediction of ketoconazole for topical or transdermal delivery employing these permeation enhancers. Based on experimental solubility values, the GastroPlus software can be applied to predict in vivo performance of the drug solution in a particular solvent (permeation enhancer) responsible for maximized solubility depending on the experimental solubility, Hansen solubility (HSPiP software), and thermodynamic parameters. (10) Moreover, the software can predict the effect of physicochemical properties of the drug for improved permeation across the human skin. Thus, the solubility of KETO in these permeation enhancers and their validation parameters (thermodynamic and computational models) are required in pre-formulation study.
In this study, HSPiP assisted to select the most relevant organic solvent (permeation enhancers) based on three solubility parameters (three-dimensional Hansen solubility and space parameters), which are designated as δd as the dispersion parameter, δp as the polarity parameter, and δh as the hydrogen parameter. The solubility study was conducted over various temperature range (T = 298.2 to 318.2 K) and fixed pressure (P = 0.1 MPa). The study was performed at a temperature below its melting point (146.7 °C) (Figure 1B). These parameters were modeled to correlate the experimental solubility data. Furthermore, the apparent thermodynamic analysis and computational models regressed the experimental data and validated the studied solubility models, respectively. Molecular interaction between the drug and solvents was also studied. Finally, the GastroPlus simulation and prediction modules investigated major factors affecting the solubility of the drug and pharmacokinetic parameters when formulated for oral or topical delivery in the best solvent.

Results and Discussion

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Characterization of KETO in the Solid Phase

KETO is a highly crystalline compound with poor aqueous solubility. The pure drug and equilibrated KETO (with methanol) were characterized for solid phases using a differential scanning calorimeter (DSC), and the result (thermogram) is illustrated in Figure 1B. A characteristic endothermic peak indicated a fusion temperature (Tfus) along with the marked value of the fusion enthalpy (ΔHfus). The observed values of Tfus and ΔHfus were 146.84 °C and 107.8 J/g, respectively, as indicated in the characteristic endothermic peak of the thermogram (Figure 1B). Moreover, these values (Tfus and ΔHfus) were observed to be 146.92 °C and 107.62 J/g (Figure 1B), respectively, for equilibrated KETO obtained from well-resolved sharp peaks. It is obvious from the thermogram that both of them (pure KETO and equilibrated) are stable and remained in a crystalline solid state. There were no visible changes in solid-state characteristic thermal parameters (Tfus and ΔHfus) during solubility assessment. The reported value of Tfus of KETO was 146.0 °C, and there is no observed degradation beyond the melting point of KETO during thermal analysis. (11) The finding is in close agreement with the experimental value (146.8 °C).

Experimental Solubility Data

The results of experimental solubility in various organic permeation enhancers are presented in Table 1. These are biocompatible and well-established skin permeation enhancers already explored in various topical and transdermal drug delivery. Moreover, several organic solvents (2-propanol, ethanol, PEG200, PEG400, and PEG600) have been investigated for improved solubility of KETO intended for pharmaceutical application. (2,12) Improved solubility in the explored permeation enhancer could be an ideal component for topical or transdermal delivery in the treatment of various dermal fungal infections. Therefore, the solubility of KETO in these permeation enhancers were envisaged and investigated for quantitative analysis followed by validation using thermodynamic and computational models. The software HSPiP assisted to screen the most suitable permeation enhancer based on the solubility parameters (dispersion, polarity, and hydrogen bond) and chemical structure of the drug (Figure 1A and Table 2).
Table 1. Mole Fractional Experimental Solubility (xe) of Ketoconazole at Varied Temperatures T = 298.2–318.2 K and Pressure = 0.1 MPaa
 temperature (K)
solvent298.2 K303.2 K308.2 K313.2 K318.2 K
ethanol2.1× 10–42.8× 10–43.7× 10–44.9× 10–45.6× 10–4
DMSO2.5× 10–42.9× 10–43.4× 10–44.2× 10–44.9× 10–4
ethylene glycol0.2× 10–40.3× 10–41.0× 10–41.3× 10–41.7× 10–4
oleic acid5.8× 10–36.3× 10–36.9× 10–37.5× 10–38.5× 10–3
span 804.7× 10–35.1× 10–35.7× 10–36.2× 10–36.9× 10–3
limonene5.1× 10–35.5× 10–36.1× 10–36.8× 10–37.3× 10–3
eugenol3.5× 10–33.7× 10–34.1× 10–34.2× 10–34.5× 10–3
THP3.2× 10–33.4× 10–33.9× 10–34.3× 10–34.9× 10–3
labrasol2.8× 10–33.1× 10–33.5× 10–33.9× 10–34.4× 10–3
propylene glycol0.1× 10–41.2× 10–41.6× 10–42.3× 10–42.8× 10–4
xidl0.38 × 10–30.53 × 10–30.74 × 10–31.01 × 10–31.37 × 10–3
a

DMSO = Dimethyl sulfoxide; THP = transcutol HP. The standard uncertainties u are u(T) = 0.10 K, u(P) = 0.004 MPa and u(xe) = 1.5%.

Table 2. Various Hansen Solubility (xe) Parameters of KTZ in Various Permeation Enhancers (Solvents)a
 Hansen solubility parameters (MPa1/2)
solventδdδpδhδRaΔδΔδ*
ketoconazole21.611.96.225.4   
ethanol15.38.919.125.115.92.2016.64
DMSO10.216.810.224.811.04.4716.89
ethylene glycol17.211.126.435.822.60.1825.67
oleic acid16.17.35.817.26.62.6117.33
span 8016.26.57.119.76.722.917.16
limonene17.22.14.318.95.922.9110.41
eugenol19.47.212.922.95.140.4112.65
THP16.37.110.221.84.132.512.93
labrasol15.84.18.720.19.323.9610.00
propylene glycol17.110.121.828.118.000.4225.50
a

IPA = isopropyl alcohol; IPM = isopropyl myristate; THP = transcutol HP; EA = ethyl acetate.

Table 1 summarizes the experimental values (xe) of KETO in the organic solvents at an explored temperature range (Table 1) wherein the values of xe were found to be constantly increasing with temperature (p < 0.05). The maximum xe solubility values of KETO were obtained in oleic acid (8.5× 10–3) and limonene (7.3× 10–3) at T = 318.2 K. The values of experimental solubility in all solvents can be ordered as oleic acid > limonene > span 80 (6.9× 10–3) > THP (4.9× 10–3) > eugenol (4.5× 10–3) > labrasol (4.4× 10–3) > DMSO (4.9× 10–4) > ethanol (5.6 × 10–4) > propylene glycol (2.8× 10–4) > ethylene glycol (1.7× 10–4) performed at a temperature of 318.2 K. The xe values followed the same trend at temperatures of T = 298.2 K, T = 303.2 K, T = 308.2 K, and T = 313.2 K. It is noticeable that the xe values were significant (p < 0.05) in oleic acid, limonene, and span 80 compared to others. This can be explained based on the correlation of the HSPs values of oleic acid, limonene, and span 80 with that of the HSPs values of pure KETO. The values of δd, δp, and δh of KETO are 21.6, 11.9, and 6.2, whereas these values for oleic acid were predicted to be 16.1, 7.3, and 5.8, respectively. The polarity parameter values of oleic acid, eugenol, span80, and THP are comparable and much lower than the hydrophilic solvents (labrasol and ethanol). KETO molar solubility values in ethanol were found to be 2.1 × 10–4, 2.8 × 10–4, 3.7 × 10–4, 4.9 × 10–4, and 5.6 × 10–4 at T = 298.2 K, T = 303.2 K, T = 308.2 K, T = 313.2 K, and T = 313.2 K, respectively. Recently, the drug molar solubility values in ethanol were reported to be 2.2 × 10–5, 2.6 × 10–5, and 2.9 × 10–5 at T = 298.2 K, T = 303.2 K, and T = 308.2 K, respectively. (2) The slight differences at the corresponding temperatures may be due to differences in pressure (0.1 MPa). However, the differences in the molar solubility with the increase in temperature were not significant, which are in accordance with the reported pattern. Moreover, Hashemzadeh and Jouyban did not investigate the molar solubility in ethanol at 298.2 and 318.2 K. (2) The drug is poorly water soluble being crystalline in nature. Therefore, the increased drug solubility may be correlated with the lipophilic–lipophilic-enabled (solute–solvent) interaction (like dissolves like). On the other hand, labrasol, ethanol, propylene glycol, and ethylene glycol exhibited quite lower values of xe, which are due to the high polarity δp value of HSPs (Tables 1 and 2) at T = 318.2 K. Oleic acid and span 80 showed about similar values of HSPs parameters, which may be a reason for closeness in experimental solubility (xe), space parameter (Ra), and total solubility (Δδ) values as shown in Table 2. (14) The mole fractional experimental solubility values of KETO in ethylene glycol and propylene glycol are 1.7 × 10–4 and 2.8 × 10–4, respectively, which may be due to higher values of δh (26.4 for ethylene glycol and 21.8 for propylene glycol) compared to KETO (6.2). This may have led to limited interaction (hydrogen bonding interaction) between the drug and solvent resulting least solubility (Tables 1 and 2). Ethylene glycol showed an approximate value of the δp (11.1), which was close to that of the drug (11.9). However, the drug was found to be the least soluble, which may be due to weak dispersion in the solvent (δp = 17.2). In this context, the drug was found maximally solubilized in oleic acid due to poor polarity of the solvent and hydrophobic–hydrophobic facilitated interaction. Thus, the solvents such as oleic acid, THP, span 80, and limonene can be proposed as suitable solvents for developing formulation intended for transdermal or topical delivery of rifampicin working as a carrier as well as permeation enhancer if laden with the drug.

Solubility Parameters of KETO and Studied Solvents using Various Models

We used all of the HSP parameters for the drug and solvents as shown in Table 2. The value of δ of KETO was predicted to be 25.4 MPa1/2 and polarity parameter was estimated to be 11.9 MPa1/2 suggesting weak interaction with hydrophilic/polar solvents. Therefore, the drug was found to have maximum xe data in a permeation enhancer with high hydrophobicity and low polarity (δp) (oleic acid, THP, span 80, and limonene). It is noteworthy that calculated values of Ra for oleic acid (6.6), span 80 (6.7), limonene (5.92), eugenol (5.14), and THP (4.13) were <10.0 MPa1/2, suggesting augmented miscibility of the drug in these solvents. In general, the value of Ra of <5.6 MPa1/2 is considered as “good soluble” or “miscible of solute”. (13,14) However, there are contradictory findings among the literature values. Few authors correlated this value as soluble (around 10 MPa1/2). (14) In the our case, the values of Ra for limonene, eugenol, THP, span 80, and oleic acid are in the range of 5.6–8.0 MPa1/2 and these could be considered as the most suitable permeation enhancers for topical or transdermal delivery. There are few reports where authors could not find any values of the Ra value close to 5.6 MPa1/2 in all explored solvents. However, they agreed and defined the solubility of the solute as soluble considering the Ra value of 8.0 close to 5.6 MPa1/2. (15) Thus, THP, limonene, span 80, oleic acid, and eugenol can be considered as a first series of solvents for good solubility/miscibility of KETO among them. Furthermore, the values of other parameters such as Δδ* and Δδ were estimated in the solvents. The values of Δδ ranged from 0.18 to 4.74 MPa1/2 for the studied solvents, which indicated within the acceptable range (<10.0 MPa1/2). This parameter (Δδ) was minimum for ethylene glycol (0.18 MPa1/2), propylene glycol (0.42 MPa1/2), and eugenol (0.41 MPa1/2), as shown in Table 2. As per the literature, the value of Δδ of <7.0 MPa1/2 was considered as the most soluble or miscible of a solute in a given solvent. (16) Considering the values of Ra and Δδ, limonene, eugenol, and THP are the most preferred solvents being capable of solubilizing hydrophobic KETO. In the case of propylene glycol and ethylene glycol, the values of Δδ, are the least but the Ra values are quite high. This might be due to the fact that the dispersion ability of the drug as observed in the δd, of the Hansen solubility parameter for eugenol (δd = 19.0) is the closest value to KETO (21.6). Similarly, the Δδ* values of KETO were determined using van Krevelen and Hoftyzer equations. However, the value of Δδ of <5.0 MPa1/2 is good for improved solubility or miscibility. (15,16) The values of Δδ* are found to be ≥10.0 MPa1/2 in all explored permeation enhancers except THP (2.93 MPa1/2) as shown in Table 2. A solvent is selected with the lowest value of Δδ* of the Hansen solubility parameter. The estimated values of Δδ* were observed to be 2.93, 10.0, and 10.41 MPa1/2 for THP, labrasol, and limonene, respectively, wherein the THP exhibited the minimum value. Thus, these Hansen solubility parameters (Ra, Δδ*, and Δδ) are in an acceptable range as compared to other solvents, which showed good solubility of KETO in THP. Thus, THP could be considered as the most suitable solvent (permeation enhancer), whereas ethylene glycol is the solvent with poor solubility of KETO. There is a correlation that exists between the solubility of a solute in a solvent and their solubility parameters. In addition, several factors are responsible for KETO solubility in the solvent and these are the molar mass volume and molecular interaction (inter and intra). (15) The objective of the study was to select a permeation enhancer with dual functionality (permeation enhancer and carrier) in developing topical or transdermal formulation. Therefore, considering Hansen solubility parameters and space parameter (Ra), THP could be the best permeation enhancer and suitable solvent when fabricated in a nanocarrier system intended for topical or transdermal delivery.

Estimation of Ideal Solubility (xidl) and Activity Coefficient (Υi)

These values were estimated to identify the most suitable solvent responsible for maximum solubility of KETO and serving as the potential permeation enhancer. Moreover, the estimated value of Υi assists to find a molecular interaction between the solute and the solvent. Initially, the xidl of KETO was estimated to calculate the value of the activity coefficient. Tables 1 and 3 summarize the values of xidl and Υi of KETO in various permeation enhancers, respectively. The ideal solubility values (xidl) of KETO were found to be 0.38 × 10–3 to 1.37 × 10–3 at T = 298.2 to 318.2 K (Table 1). The experimental solubility xe of KETO in oleic acid was found to be significantly (p < 0.05) higher than the ideal solubility (xidl) values at T = 298.2 and 303.2 K, whereas this pattern decreases beyond the temperature of 303.2 K (Table 1). Ethanol, DMSO, ethylene glycol, and propylene glycol showed experimental solubility values of KETO lower than the ideal solubility as shown in Table 1. Similarly, oleic acid, span 80, limonene, eugenol, and THP exhibited significantly (p < 0.05) higher values of xe as compared to xidl over all studied temperature points, which could be basis for considering these solvents suitable for KETO solubilization.
Table 3. Activity Coefficient (Υi) of Ketoconazole at Varied Temperatures (T = 298.2–318.2 K)a
 Υi
solvent298.2 K303.2 K308.2 K313.2 K318.2 K
ethanol1.811.891.982.052.44
DMSO1.521.832.162.412.79
ethylene glycol1.933.657.357.758.06
oleic acid1.651.841.761.842.61
span 800.801.041.281.622.21
limonene0.740.961.201.481.87
eugenol1.001.431.691.851.98
THP0.110.560.881.031.18
labrasol1.351.712.102.583.11
propylene glycol3.804.434.594.834.98
a

DMSO = dimethyl sulfoxide; THP = transcutol HP.

The estimated values of activity coefficient (Υi) of KETO in 10 permeation enhancers at the temperature range of T = 298.2–318.2 K are tabulated in Table 3. The values were in the range of 0.75–1.87, 1.0–1.98, and 0.11–1.18 in limonene, eugenol, and THP, respectively. Moreover, the Υi values were relatively higher in DMSO, ethylene glycol, propylene glycol, labrasol, and ethanol as compared to THP, limonene, and eugenol estimated at T = 298.2 K, 303.2, 308.2, 313.2, and 318.2 K. That may rationalize that these three solvents might have maximized the solute–solvent molecular interaction, which can be ordered as “KETO-THP > KETO-limonene > KETO-Eugenol” combination. Improved solubilization in THP may be attributed to formation of intermolecular hydrogen bonding between the hydroxyl group of THP and the imidazole nitrogen atom. (18,19) Conclusively, THP, limonene, and eugenol may be the most preferred solvents to solubilize KETO.

Computational Validation

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The objective of the study was to investigate a suitable permeation enhancer working as a solvent to solubilize KETO and a potential skin permeation when formulated as topical or transdermal formulation. Therefore, experimental solubility data were generated at various temperatures (selected based on Hansen solubility parameters). The data needed to be validated using two known validation computational models such as the Apelblat model and vanʼt Hoff model. Using both of them, a graphical correlation was established between the lnxe and lnxapl of KETO as a function of 1/T (Figure 2). The computational validation results are presented in Table 4, which corroborated a good correlation between lnxe and lnxapl (Figure 2). Moreover, the estimated values of the percent relative mean square deviation (%RMSD) and overall %RMSD of the drug in all studied solvents were 0.011–0.848 and 0.136, respectively (Table 4). In Table 4, the values of A, B, and C represent the Apelblat solubility parameters, which were estimated using the Apelblat equation. To analyze this model for each solvent, the value of r2 (regression coefficient) was found to be ≥0.99, vindicating a good correlation of lnxe of KETO in all studied solvents.

Figure 2

Figure 2. Correlation of lnxe values of ketoconazole with the Apelblat model in various organic solvents as a function of 1/T.

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Table 4. Apelblat Equation Parameters for Various Permeation Enhancers (Solvent)a
 parameters
solventABCr2RMSD (%)overall RMSD
ethanol–317.004–6.12955.9880.99890.037 
DMSO–211.412–7.13737.5200.99970.039 
ethylene glycol–139.297–7.16124.4690.99930.345 
oleic acid–225.371–8.15140.5530.99780.018 
span 80–188.187–9.14233.8410.99950.0130.136
limonene–194.879–7.13135.0850.99980.012 
eugenol–183.983–7.12615.3570.99760.026 
THP–140.569–6.13525.2170.99990.011 
labrasol–137.419–8.14729.6060.99970.016 
propylene glycol–227.878–7.14240.0480.99320.848 
a

DMSO = dimethyl sulfoxide; THP = transcutol HP; RMSD = root mean square deviation.

Similar experimental analysis was carried out using the vanʼt Hoff model wherein a graphical correlation between lnxe and lnxvant as a function of 1/T was demonstrated, suggesting a good correlation (Figure 3). Likewise, the estimated values of the %RMSD, overall %RMSD, model parameters (a and b), and regression coefficient are presented in Table 5. The estimated values of %RMSD and overall %RMSD were found to be 0.011–0.178 and 0.0478, respectively (Table 5) for all studied solvents. The estimated values of r2in each solvent were found to be ≥0.09. Thus, both models validated the experimental solubility data studied in various solvents at varied temperatures by establishing a good graphical correlation and estimating model parameters.

Figure 3

Figure 3. van’t Hoff plot for ketoconazole plotted between lnxe and (1/T – 1/Thm) for the drug in various organic solvents.

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Table 5. Vanʼt Hoff Model and Parametersa
 parameters
solventabr2RMSDoverall RMSD
ethanol58.84–17256.20.98880.041 
DMSO41.062–11546.00.99980.042 
ethylene glycol52.119–14865.80.99890.076 
oleic acid47.545–12489.50.99730.178 
span 8048.508–13094.30.99980.0230.0478
limonene41.238–10805.40.99750.013 
eugenol19.403–4744.860.99390.013 
THP29.123–7763.60.99990.010 
labrasol28.137–7577.060.99980.017 
propylene glycol26.376–7589.080.97760.065 
a

DMSO = dimethyl sulfoxide; THP = transcutol HP.

Thermodynamic Parameters

Thermodynamic functional parameters are required to explain the mechanistic view of KETO solubility in individual solvent at various temperatures. These function parameters are based on physical changes (events) and represented as ΔsolΔG°, ΔsolΔH° and ΔsolΔS° in a mathematical equation. We rationalized the process of KETO solubility in studied solvents by thermodynamic analysis and using three thermodynamic solubility function parameters. (20) These functional parameters were estimated for KETO in various solvents and are presented in Table 6. The calculated values of ΔsolΔG°, ΔsolΔH° and ΔsolΔS° were found in the range of 1195.7–10820.7, 13071.9–22501.2, and 28.4–56.92 kJ mol–1, respectively, in the investigated solvents. It is apparently clear from the result that oleic acid, span 80, limonene, eugenol, and THP showed relatively low values of the free energy (ΔsolΔG°) of dissolution as compared to other solvents. Similarly, limonene, eugenol, and THP showed the values of ΔsolΔS° to be 27.07, 22.34, 20.2 kJ mol–1, respectively, which were the minimum values among them. These solvents can be ordered for ΔsolΔS° as limonene > eugenol > THP, suggesting THP as the most suitable solvent for KETO. The estimated values of ΔsolΔS° were the maximum in ethanol, DMSO, ethylene glycol, and propylene glycol, which indicated that these solvents could be considered as solvents for poor solubility of KETO due to hydrophilicity and high polarity solvent resulting in weak solute–solvent molecular interaction (Table 6). As per the concept of thermodynamics, a reaction or a process is said to be spontaneous (negative free energy) when the change in free energy ΔsolΔG° decreases. Thus, KETO solubilization in limonene, THP, and eugenol was a spontaneous process resulting in a significant change in ΔsolΔG°, providing a suitable thermodynamic environment for increased solubility. (20) In addition, the lower values of ΔsolΔS° for THP, limonene, and eugenol further supported a reasonable explanation for the increased solubility of KETO in these permeation enhancers. It is quite interesting to note that the negative enthalpy values of dissolution in limonene, eugenol, and THP may be due to the possible hydrophobic interaction with the non-polar functional groups (methyl, methylene, and aromatic rings) of KETO as shown in Figure 1A. (21) Apart from these, there are several factors responsible for the solubility of KETO in these solvents or permeation enhancers. These are physicochemical behavior of the solute and solvent, hydrogen bond formation with non-polar groups of the drug, solute–solvent interaction, and co-solvency using a binary mixture of organic solvent with water. Very recently, it was reported that ethanol used as co-solvent with water increased the solubility of KETO due to breaking the ordered structure of water stabilized with hydrogen bonding around the non-polar groups of KETO, which caused increased values of enthalpy and entropy of the system. (21)
Table 6. Summary of Thermodynamic Functional Parameters for Validationa
 parameters
solventΔsol ΔH° (kJ mol–1)Δsol ΔG° (kJ mol–1)Δsol ΔS° (kJ mol–1)r2
ethanol–4773.9–20115.7651.330.9767
DMSO–3254.3–20461.356.410.9948
ethylene glycol–10820.0–19373.258.040.9357
oleic acid–1778.8–14273.3430.960.9987
span 80–1826.8–13267.237.510.9975
limonene–1763.6–13071.8927.070.9947
eugenol–1195.7–14109.022.340.9753
THP–1982.3–14243.4220.200.9998
labrasol–2150.0–14519.840.550.9982
propylene glycol–5138.1–22501.256.920.9865
a

DMSO = dimethyl sulfoxide; THP = transcutol HP.

GastroPlus Prediction Studies

The software program is basically to simulate in vitro data and prediction of in vivo performance based on the input parameters (Table 7). We added the values of in vitro drug release in in vitro data tab for pure KETO and THP-solubilized drug. Neat KETO (suspension) exhibited % drug releases of 8.4, 12.0, 25.1, 31.6, and 39.9% at the time points of 0.5, 1, 2, 4, and 8 h, respectively, in phosphate buffer solution (pH 7.4). Similarly, THP-solubilized KETO exhibited % drug releases of 25.7, 56.9, 67.3, 75.2, and 87.7% at the same time points. The release data was also modeled for the Weibull release distribution pattern using the GastroPlus simulation. The results are illustrated in Figure 4A,B. Figure 4A and Figure 4B shows the in vitro release pattern of the neat KETO suspension and THP-solubilized drug (10 mg/mL), respectively. The neat KETO suspension and THP-solubilized drug revealed maximum drug releases of 39.9 and 87.7% at the end of 8 h, respectively. The Weibull-modeled graph (single Weibull) showed that the release distribution followed a sigmoidal pattern as evidenced with shape factors (b shape values) of 1.47 and 1.57, for suspension and THP-solubilized KETO (blue solid lines of Figure 4A,B). It is obvious from the release graphs that this model may not be the only prefect release model to confirm immediate and controlled release behavior of the drug. However, all of the other parameters affecting the drug release (such as pH, amount, pKa, polarity, logP, density, and temperature) should be figured out and controlled. (22,23)

Figure 4

Figure 4. GastroPlus-based simulation and prediction study: (A) In vitro drug release behavior and Weibull model distribution of neat ketoconazole suspension (blue line for sigmoidal release pattern), (B) in vitro drug release behavior and Weibull model distribution of THP solubilized ketoconazole (blue line for sigmoidal release pattern) in buffer solution (pH 7.4), (C) skin absorption of neat ketoconazole from suspension, and (D) skin absorption of THP-solubilized ketoconazole.

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Table 7. Summary of the Input Parameters of Ketoconazole for the GastroPlus-Based Prediction Study
input parametersvalue
empirical formulaC26H28Cl2N4O4
molecular weight (g/mole)531.04
melting point (°C)146
log P value4.35
pKa3.96 (amine) and 6.74 (imine)
aqueous solubility (mg/ml at 25 °C)0.24
apparent permeability (×10–4 cm/s)0.75
dosing volume (mL)1.0
dose (mg)2.0
body weight (Kg)60.0
total clearance (L/h)8.66
elimination half-life (h)8.0
volume of distribution (L/Kg)0.36 (25.41 L)
protein binding capacity (%)84
simulation time (h)12
Furthermore, the software PBPK model predicted the amount of the drug permeated across human skin (70 Kg) when applied to the skin (arm). The predicted values of KETO cream (considering pure drug = 0.2 mg) and THP-solubilized KETO (0.2 mg as solution) are illustrated in Figure 4C and 4D, respectively where the neat drug cream and THP-solubilized KETO showed 38.0% and 79.1%, respectively. This may be correlated with improved solubilisation and permeation potential of THP explored for several poor soluble drugs. This skin penetration and permeation may be attributed to the facilitated drug portioning and diffusion. The THP is reported as the most suitable skin permeation enhancer possibly due to capable of increasing flux (21 times higher) and diffusion coefficient (17 times) higher than the hydrated skin. (23)
The neat KETO is a hydrophobic and weak water soluble molecule. However, THP-solubilized KETO was anticipated to have high permeation across human skin on topical application and enhanced absorption through intestinal membrane when administered oral. Therefore, the software based prediction study suggested that the dissolution rate (0.1 mg as input parameter of topical dose) of the drug and skin absorption (at pH 5.6 as simulated pH of human skin) was within 1 h as shown in Figure 5. The inset graph of Figure 5 depicted the immediate absorption (in vivo) profile of THP-solubilized KETO when administered orally. This could be possible due to improved drug solubility and enhanced permeation attributed to the solvent (THP). (23) However, the preclinical study using a suitable animal requires generating a complete proof of concept for topical/transdermal/oral formulation of KETO using THP as a solvent and permeation enhancer.

Figure 5

Figure 5. GastroPlus-based prediction of a relationship between dissolution and skin permeation of ketoconazole dissolved in THP. The inset of the figure predicted the plasma concentration time profile of THP solubilized ketoconazole when administeresd orally (0.1 mg).

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Significance of the Explored Permeation Enhancers

In this study, the term “solvent” was used collective for the organic solvent, lipid, and surfactants responsible for improved solubilization and skin permeation if laden with the drug. KETO is a choice drug for several topical fungal diseases, which need to be addressed with new excipients exhibiting dual functionality such as solubilization as well as skin permeation. Based on the Hansen solubility parameter, 10 solvents were predicted for KETO solubility and possible interaction. The solubility experimental data were validated using thermodynamic functional terms and computational models. Thus, the result of this study would assist formulation scientists (transdermal and topical) during the preliminary study for the selection of the organic phase considering the solubility and skin permeation enhancer. We found limonene (terpene), eugenol, and THP as the most suitable solvents (permeation enhancer) intended for topical and transdermal formulation. In several literature studies, these excipients are well established for the skin permeation potential of poor soluble drugs. There is scarcity of in vivo data in human to establish a direct correlation with in vitro findings. However, we predicted in vitro release kinetics, the drug absorption across human skin (left arm), and compared between the neat drug and THP-solubilized KETO using the GastroPlus predictive modules.

Conclusions

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KETO is extremely poorly soluble in water and a well-established antifungal candidate to control cutaneous fungal infections. Data of experimental and Hansen solubility parameters suggested that several permeation enhancers can be a suitable option for the drug solubilization and skin permeation enhancing effect. The thermodynamic functional parameters and computational models validated the experimental solubility carried out at varied temperature. No transformation occurred in KETO extracted from methanol as evidenced by the DSC result. Two models such as the vanʼt Hoff and Apelblat were employed to validate the results of experimental solubility. All of the solvents exhibited a significant (p < 0.05) proportional relationship of the experimental solubility values with temperature. This may be rationalized that these three solvents were found to have maximum solute–solvent molecular interaction, which can be ordered as KETO-THP > KETO-limonene > KETO-Eugenol combination at T = 318.2 K as compared to other combinations. The GastroPlus program software predicted a maximized drug content permeated (THP solubilized) in human skin as compared to the drug solution. Moreover, there was a good correlation between in vitro drug dissolution and permeation (absorption across the skin) when predicted for THP-solubilized construct (immediate release pattern < 1 h). The software predicted an immediate release type of oral absorption for THP-solubilized KETO. The findings suggested that transcutol may also be an ideal alternative as solvent and skin permeation enhancer for topical delivery of KETO to control fungal infection.

Experimental Methods

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Materials

KETO was procured from Sigma-Aldrich, (India). Transcutol HP and labrasol were obtained as ex gratia from Gatteffosse (36 chem de Genas-BP 603-F-69804 Saint Priest Cedex France). Span 80, ethanol, ethylene glycol, oleic acid, eugenol, limonene, DMSO, and ethanol were purchased from Merck Chemicals Mumbai, India. All of the reagents were of analytical grade.

Analytical Methodology

The drug was assayed using a validated HPLC (high-performance liquid chromatography, Waters, Empower 2 software, USA), and the procedure was adopted as per the reported method. (24) Analysis was performed using a reverse phase C18 column (150 mm × 46 mm, 5 μm), at a flow rate of 1 mL/min and UV detector at 254 nm. The mobile phase was composed of acetonitrile, water, and diethylamine (70:30:0.05, v/v). The mobile phase was filtered, sonicated, and then used in the system using 10 μL as the injection volume (sample). The set run time was 10 min with a constant operating temperature of 20 ± 1 °C (Figure 1C). The sensitivity of the analysis was 0.005 to 0.010 μg/mL with a regression coefficient (r2) of 0.9999. The final pH of the mobile phase was adjusted to 9.0 using a 0.01 N NaOH solution. (25)

Differential Scanning Calorimeter: Thermal Analysis

In order to observe any possible transition in analytical solvent, pure KETO was completely recovered from the equilibrated KETO in methanol (slow evaporation method) and assessed for thermal parameters (fusion temperature and enthalpy) using a DSC method (DSC-50, Shimadzu, Japan). This analysis was conducted to find probable chances of transition in the explored organic solvents, possible impurities, and drug degradation over the studied temperature range. An accurately weighed amount (4.0 mg) of both samples (pure and recovered) were transferred into an aluminum pan, sealed (hermatically), and then kept in the furnace chamber (sample holder). The samples were heated at the heating rate of 10 °C/min till 200 °C followed by cooling after completion of heating (nitrogen flow of 20.0 mL/min) for the next sample. The result of DSC was presented in DSC spectral peaks containing the values of endothermic peaks and fusion enthalpy (ΔHfusion J/g). The DSC cell was calibrated using indium (melting point of 156.8 °C and ΔHfusion of 28.71 J/g).

Solubility Assessment

The experimental solubility (xe) of KETO was studied in PG (propylene glycol), labrasol, THP (transcutol HP), eugenol, limonene, span 80, oleic acid, ethylene glycol, DMSO, and ethanol, which are of GRAS (generally regarded as safe) organic solvents and major skin permeation enhancer in topical formulations. The study was performed at five temperature points (T = 298.2, 303.3, 308.2, 313.2, and 318.2 K) and constant pressure (0.1 MPa) following the reported method. (7) In brief, the weighed amount of KETO was added to 5 mL of each organic solvent separately followed by shaking in a water bath shaker for 12 h (Remi Equipment Pvt. Ltd., Mumbai, India). The study was continued till equilibrium was attained between the dissolved and undissolved KETO. The dissolved content (μg g–1) was estimated using validated HPLC at a λmax of 254 nm. Analysis was carried out in triplicate (n = 3) for mean and ± SD values.
(1)
where m1 and M1 are the mass and the molar mass of KETO, respectively. Similarly, m2 and M2 represent the mass and the molar mass of the solvent, respectively.

Solubility Parameters

Hildebrand and Scott introduced the idea of the solubility parameters based on the solubility behavior of the solute in a specific solvent. (26) Hildebrand and Scott considered that the inherent cohesive energy (criterion of attractiveness) of any solute is a necessary factor to separate molecules or ions or atoms from the parent compound and is related to the solubility parameters. (27) It is noticeable that the solubility of any solute is maximum when the difference between the polarity parameter of the solute (δps) and the solvent is approximately zero [Δ(δps – δpv) = 0]. (10) The Hildebrand principle could be applied to the simple liquid mixture being used in pharmaceutical manufacturing such as oral solution, parenteral product, and topical formulation (solution). However, this concept does not fit for the complex pharmaceutical mixture based products. For this, the principle was further extended by establishing new approach named as the Hansen approach to understand the complex mixture and associated interactions between the solute and the solvent. Theoretically, the Hansen theory depends upon the divided individual component of the total cohesive energy (δt) arising from the dispersion force (δd), molecular dipole–dipole interactions (δp) and the hydrogen bond (δh). (28)
(2)
In a new approach, the three-dimensional Hansen solubility parameter (3D-HSP, δ) was obtained by the sum of the square of the individual parameters:
(3)
Thus, 3D-HSP (δ) of KETO and individual solvent was calculated using HSPiP software (version 5.0.1, Louisville, KY, USA) using eq 3. The individual parameters such as dispersion, polarity, and hydrogen bonding are indicated as δd, δp, and δh, respectively, which are three prime Hansen solubility parameters responsible for main interactions between the solute and organic solvent.
During product development and generation proof of concept, researchers and formulation scientists need to understand the basic fundamental working in the solubility and the molecular interactions. These interactions exist between the solute–solvent, solvent–polymer, and solute–solvent. Thus, there are various established approaches based on the concept of solubility parameters or the “like dissolves like” theory. Van-Krevelen and co-workers presented a modified solubility parameter Δδ for explaining the mixing mechanism of two substances by eq 4. (16,17)
(4)
In order to describe the maximum probable miscibility of the solute in the solvent or between the two components, a threshold reported to be Δδ ≤ 5.0 MPa1/2, wherein the Δδ value could be considered less miscible or higher than 10, is regarded as immiscible. In this context, the term “miscibility” refers to a solution comprising of a solute (of certain molar concentration) in a particular solvent at a certain temperature.
In addition, Bagley presented a conceptual thermodynamic relationship between two solubility parameters (δd and δp). This is known as a combined solubility parameters (δv) as given in eq 5:
(5)
Equation 5 can be applied to project the 3D solubility parameter space (Ra) into a 2D plot. This plot was drawn between δv and δh, known as Bagley plot. This Ra was used to estimate a level miscibility or solubilization between two components or substances. The solubility parameter space (Ra) is a distance in the Bagley plot, which represents the solubility of any solute in a particular solvent. Mathematically, the value of Ra can be determined using eq 6:
(6)
Notably, this equation (Bagley plot) was the best fit model to estimate the solubility/miscibility of a polymer or an active drug or solute in a particular solvent/excipient. Furthermore, Greenhalgh established a new model for the miscibility of two substances, which was based on the differences of Δδt (the total solubility parameters). This can be calculated using eq 7:
(7)
In this model, it was established that two substances or compounds are said to be completely miscible when Δδt ≤ 7.0 MPa1/2 and immiscible when Δδt ≥ 10.0 MPa1/2. It is crucial to divide Δδt into its components (δd, δp, and δh), and the major limitation of this approach is the estimation of partial solubility.
Ideal solubility (xideal) and activity coefficient (Υi)
Fundamentally, a compound or substance or solute is considered in an equilibrium state of an ideal solution. Moreover, the free energy (G) or partial molar G of any compound or substance (crystalline solute) must be equal to the saturated solution of the same solute, which can be expressed as eq 8:
(8)
In the case of an irreversible process, the total energy of such process is the sum of all involved reversible processes between the same points (Kirchoffʼs law). That is why the irreversible enthalpy (at temperature T as melting point of the solute) represents the sum of all reversible enthalpies. The xideal of any solute in a particular organic solvent or permeation enhancer can be presented as eq 9
(9)
where ΔHm, ΔCpm and Tm are the enthalpy of melting, the difference of the molar heat capacity of the solid state with that of the liquid state, and the fusion temperature of the solute, respectively. (29)
Mathematically, the value of ΔCpm can be estimated using eq 10
(10)
where the values of Tm and ΔHm were estimated to be 419.0 K and 57.28 kJ mol–1, respectively (Figure 1B) by DSC analysis. Thus, the calculated value of ΔCpm for pure KETO was 43.79 J mol–1 K–1 using eq 10. Notably, it is obvious from eq 9 that an ideal solubility or the crystal–liquid solubility ratio is dependent upon the melting point of the solute only and the solvent has no effect. (30) The values of xideal and activity coefficient (Υi) of KETO were estimated in various solvents using eqs 9 and 11, respectively:
(11)

Computational Validation

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In the present study, the experimental solubility was estimated in various organic solvents (permeation enhancers), which need to be validated using computational validation models. These models (Apelblat model and vanʼt Hoff model) are based on a thermodynamic concept. (31,32) The apelblat solubility (xapl) of KETO was calculated using eq 12:
(12)
where A, B, and C are the Apelblat solubility parameters estimated from the experimental solubility data (Table 1) using the nonlinear multivariate regression analysis method. The xe values of KETO in various solvents were modeled with the xapl data using relative means square deviation (% RMSD) and regression r2 values (Figure 2). The % RMSD values can be estimated using eq 13
(13)
where N is the number experimental data points in the current study. Similarly, the vanʼt Hoff model solubility was estimated using eq 14
(14)
where a and b are the vanʼt Hoff solubility parameters at temperature T and estimated by plotting the ln(xe) value of KETO as function of 1/T (K).

Thermodynamic Parameter Assessment

It was required to assess the thermodynamic terms (Gibbs free energy, enthalpy, and entropy) for KETO in each solvent at the studied temperature. Generally, up to now, explanation of thermodynamic function parameters (terms) for the noted molecule was lacking in the literature. Therefore, these functional parameters as validation tools for the experimental solubility have been taken into consideration and there are the scarcity of quantitative thermodynamics data for the drug in previous reports. In this study, an attempt has been made to fill this gap for the assessment of the solubility parameters. Fundamentally, a solution is said to be an ideal solution when the change of entropy, volume, and energy on mixing is null. Therefore, thermodynamic functional parameters of the solubilized KETO in a particular solvent forming a non-ideal solution can be used to characterize them, which are apparent standard dissolution enthalpy (ΔsolH°), apparent standard dissolution entropy (ΔsolS°), and apparent standard Gibb free energy (ΔsolG°). These parameters were estimated through the apparent thermodynamic analysis method for KETO in a particular organic solvent over the explored temperature range. Moreover, the values of these parameters (ΔsolH°, ΔsolG°, and ΔsolS°) were determined using the vanʼt Hoff and Krug models. (33) It was required to estimate the value of ΔsolH° for KETO in an individual solvent at mean harmonic temperature (Thm = 305.0 K) using the vanʼt Hoff analysis model (eq 15). (29)
(15)
where R and Thm are the gas constant (8.314 J K–1 mol–1) and the mean harmonic temperature, respectively. The enthalpy of dissolution (ΔsolH°) was calculated using the vanʼt Hoff plot. Moreover, the value of ΔsolG° for KETO was calculated using the Krug et al. (33) analysis model (eq 16) in each organic solvent at Thm:
(16)
The intercept value was estimated from the vanʼt Hoff plot in each solvent (Figure 3).
Similarly, the ΔsolS° value of KETO was calculated using eq 17. (33)
(17)

GastroPlus Prediction Software: In Silico Study

The GastroPlus software (version 9.7, Simulation Plus, Inc., Lancaster, USA) simulates in vitro data to in vivo performance using the ACAT (advanced compartmental absorption and transit) model based on physiological-based oral absorption model comprising nine compartmental segments of gastrointestinal tract (GIT). The software estimates and predicts pharmacokinetic parameters using PKPlus modules based on the input parameters. The program provides three tabs (compound, physiological, and pharmacokinetics tabs) for data input before analysis. There are several by-default parameters, literature-based input values, and experimental data, which are processed for simulation and prediction. The PSA module (parameter sensitivity analysis) predicts the effect of physiochemical properties (solubility, particle size, shape, density, pH, pKa, logP, etc.) of the compound, the effect of the physiological condition (intestinal transit time, volume, fast and fed condition), and effect of formulation (nanoeffect, particle size, permeability coefficient) on PK parameters.
In this study, a prediction study was carried out using experimental data, ADMET predictor module-based suggested values, and literature data. The permeation enhancer or solvent exhibiting maximum solubility of KETO was used as a new construct and compared to pure KETO for oral as well as transdermal delivery. The input parameters of the drug are presented in Table 5 obtained from various literature sources. For prediction of transdermal performance, a new additional route module was used.

Statistical Analysis

All of the experiments were repeated to get mean and standard deviation values. Data were statistically analyzed using the Kruskal–Wallis analysis and Dennʼs test. MINITAB (version 15.0, free trial version) was employed to run nonlinear regression analysis using experimental values. The HSPiP software (version 5.2.06) estimated the Hansen solubility parameters of KETO and organic solvents. The value was considered significant at p < 0.05 in the study.

Author Information

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  • Corresponding Authors
  • Authors
    • Mohd Neyaz Ahsan - Department of Medical Laboratory Technology University Polytechnic, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
    • Raisuddin Ali - Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
    • Mohd Usman Mohd Siddique - Department of Pharmaceutical Chemistry, Shri Vile Parley Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharastra, India
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research was funded by the Researchers Supporting Project (RSP-2020/146) at King Saud University, Riyadh, Saudi Arabia.

Abbreviation

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KETO

ketoconazole

BCS

biopharmaceutical classification system

DSC

differential scanning calorimeter

THP

transcutol HP

RMSD

root-mean-square deviation

HPLC

high-performance liquid chromatography

DMSO

dimethyl sufoxide

PK

pharmacokinetics

References

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This article references 33 other publications.

  1. 1
    Bongomin, F.; Gago, S.; Oladele, R.; Denning, D. Global and multi-national pre-valence of fungal diseases—estimate precision. J. Fungi 2017, 3, 57,  DOI: 10.3390/jof3040057
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Hashemzadeh, N.; Jouyban, A. Solubility of Ketoconazole in Ethanol + Water Mixtures at Various Temperatures. Chem. Eng. Commun. 2015, 202, 1211– 1215,  DOI: 10.1080/00986445.2014.912636
    Google Scholar
    2
    Solubility of Ketoconazole in Ethanol + Water Mixtures at Various Temperatures
    Hashemzadeh, Nastaran; Jouyban, Abolghasem
    Chemical Engineering Communications (2015), 202 (9), 1211-1215CODEN: CEGCAK; ISSN:0098-6445. (Taylor & Francis, Inc.)
    Ketoconazole is an important drug with low water soly. Its low aq. soly. could be increased using various methods such as by the addn. of a pharmaceutical cosolvent. The soly. of ketoconazole in ethanol + water mixts. at 293.2, 298.2, 303.2, and 308.2 K were detd., and the addn. of ethanol increased the soly. and the max. value was obtained at 80% of ethanol. The generated data were math. represented using the Jouyban-Acree model within an acceptable accuracy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotFCgurs%253D&md5=a3d7ef286e40c2ef7ff455bc9bc8a688
  3. 3
    Jacobs, G. A.; Gerber, M.; Malan, M. M.; du Preez, J. L.; Fox, L. T.; du Plessis, J. Topical delivery of acyclovir and ketoconazole. Drug Delivery 2016, 23, 631– 641,  DOI: 10.3109/10717544.2014.933283
    Google Scholar
    3
    Topical delivery of acyclovir and ketoconazole
    Jacobs, Gerda A.; Gerber, Minja; Malan, Maides M.; du Preez, Jan L.; Fox, Lizelle T.; du Plessis, Jeanetta
    Drug Delivery (2016), 23 (2), 631-641CODEN: DDELEB; ISSN:1071-7544. (Taylor & Francis Ltd.)
    Context: Viral and fungal cutaneous manifestations are regularly encountered in immunocompromised human immunodeficiency virus/acquired immunodeficiency syndrome individuals and can be treated by drugs such as acyclovir and ketoconazole, resp. Objective: The aim of this study was to det. whether the novel Pheroid delivery system improved the transdermal delivery and/or dermal delivery of acyclovir and ketoconazole when incorporated into semi-solid formulations. Materials and methods: Semi-solid products (creams and emulgels) contg. these drug compds. were formulated, either with or without (control) the Pheroid delivery system. The stability of the formulated semi-solid products was examd. over a period of six months and included the assay of the actives, pH, viscosity, mass loss and particle size observation. Vertical Franz cell diffusion studies and tape stripping methods were used to det. the in vitro, stratum corneum (SC)-epidermis and epidermis-dermis delivery of these formulations. Results and discussion: Stability tests showed that none of the formulations were completely stable. Acyclovir showed a biphasic character during the in vitro skin diffusion studies for all the tested formulations. The Pheroid cream enhanced the transdermal, SC-epidermis and epidermis-dermis delivery of acyclovir the most. The av. amt. of ketoconazole diffused over 12 h showed improved delivery of ketoconazole, with the Pheroid emulgel exhibiting the best transdermal and epidermis-dermis delivery. Conclusion: The Pheroid formulas increased transdermal penetration as well as delivery to the dermal and epidermal skin layers. The Pheroid emulgel and the Pheroid cream increased the topical delivery of ketoconazole and acyclovir, resp.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XoslagsA%253D%253D&md5=10046222ca6d774c0fc5da0ce06c0f6e
  4. 4
    Durden, F. M.; Elewski, B. Fungal infections in HIV-infected patients. Semin. Cutaneous Med. Surg. 1997, 16, 200– 212,  DOI: 10.1016/S1085-5629(97)80043-0
    Google Scholar
    4
    Fungal infections in HIV-infected patients
    Durden F M; Elewski B
    Seminars in cutaneous medicine and surgery (1997), 16 (3), 200-12 ISSN:1085-5629.
    Opportunistic fungal infections are commonly encountered in the acquired immunodeficiency syndrome (AIDS) patient population. Fungal infections in the patient infected with the human immunodeficiency virus (HIV) are a major cause of morbidity and mortality. The yeasts Candida and Cryptococcus neoformans, the dimorphic fungi Histoplasma capsulatum and Sporothrix schenckii, and the dermatophyte fungi are the most common pathogenic fungi in patients infected with HIV. The characteristics of these and other relevant mycotic pathogens, and their clinical presentation are discussed. Mycoses in the patient infected with HIV are often atypical, and can be masked by other infections. Cutaneous manifestations may provide valuable diagnostic clues. The clinician must maintain a high index of suspicion to establish an early diagnosis and rapidly institute therapy. Treatment may suppress rather than cure the mycosis, because host immunity in conjunction with antifungal agents is necessary to eliminate infection.
    >> More from SciFinder ®
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  5. 5
    Hossin, B.; Rizi, K.; Murdan, S. Application of Hansen Solubility Parameters to predict drug–nail interactions, which can assist the design of nail medicines. Eur. J. Pharm. Biopharm. 2016, 102, 32– 40,  DOI: 10.1016/j.ejpb.2016.02.009
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    5
    Application of Hansen Solubility Parameters to predict drug-nail interactions, which can assist the design of nail medicines
    Hossin, B.; Rizi, K.; Murdan, S.
    European Journal of Pharmaceutics and Biopharmaceutics (2016), 102 (), 32-40CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    We hypothesised that Hansen Soly. Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) det. the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/soly. in org. liqs., (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of exptl.-detd. affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match exptl. reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Soly. Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.
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  6. 6
    Jouyban, A.; Soleymani, J.; Soltanpour, S. Solubility of Ketoconazole in Polyethylene Glycol 200 + Water Mixtures at 298.2–318.2 K. J. Solution Chem. 2014, 43, 950– 958,  DOI: 10.1007/s10953-014-0171-6
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    6
    Solubility of ketoconazole in polyethylene glycol 200 + water mixtures at 298.2-318.2 K
    Jouyban, Abolghasem; Soleymani, Jafar; Soltanpour, Shahla
    Journal of Solution Chemistry (2014), 43 (5), 950-958CODEN: JSLCAG; ISSN:0095-9782. (Springer)
    The soly. of ketoconazole in binary mixts. of polyethylene glycol 200 (PEG 200) + water is reported at temps. ranging from 298.2 to 318.2 K. The Jouyban-Acree model and its combined version including the van't Hoff equation were used for correlating the reported data; the obtained mean relative deviations are 9.5 and 9.9 %, resp. Also, two previously trained versions of the Jouyban-Acree model were used for predicting the reported data points in which the prediction errors were 34.6 and 31.0%.
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  7. 7
    Soltanpour, S.; Nazemi, V. Solubility of Ketoconazole in Binary and Ternary Solvents of Polyethylene Glycols 200, 400 or 600 with Ethanol and Water at 298.2 K. Data Report and Analysis. J. Solution Chem. 2018, 47, 65– 79,  DOI: 10.1007/s10953-017-0708-6
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    7
    Solubility of Ketoconazole in Binary and Ternary Solvents of Polyethylene Glycols 200, 400 or 600 with Ethanol and Water at 298.2 K. Data Report and Analysis
    Soltanpour, Shahla; Nazemi, Vahideh
    Journal of Solution Chemistry (2018), 47 (1), 65-79CODEN: JSLCAG; ISSN:0095-9782. (Springer)
    The solubilities of ketoconazole in binary and ternary mixts. of water, ethanol and polyethylene glycols 200, 400 or 600 (185 data points) were detd. at 298.2 K. Williams-Amidon and Jouyban-Acree cosolvency models were used to model the data, with overall mean relative deviations (OMRDs) for the soly. data in binary and ternary solvents of 17.5 and 23.5%, resp. For predicting the soly. data of ketoconazole the trained versions of the models were used and the OMRD values were 47.7 and 33.0%, resp.
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  8. 8
    Lane, M. E. Skin penetration enhancers. Int. J. Pharm. 2013, 447, 12– 21,  DOI: 10.1016/j.ijpharm.2013.02.040
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    8
    Skin penetration enhancers
    Lane, Majella E.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2013), 447 (1-2), 12-21CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    A review. The skin has evolved to prevent excessive water loss from the internal organs and to limit the ability of xenobiotics and hazardous substances to enter the body. Notwithstanding this barrier function, a no. of strategies have been developed by scientists to deliver drugs to and through the skin. The aim of this review is to consider the various types of chem. penetration enhancers (CPEs) which have been investigated in the scientific literature. Potential pathways for CPEs to exert their action are examd. with ref. to the phys. chem. of passive skin transport. The emphasis is on those studies which have focussed on human and porcine skin because of the limitations assocd. with skin permeation data collated from other species. Where known, the mechanisms of action of these compds. are also discussed. Examples of enhancers used in com. topical and transdermal formulations are provided. It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a Diffusion-Partition-Soly. theory. Finally, some of the limitations of studies in the literature are considered and the importance of monitoring the fate of the penetration enhancer as well as the active is highlighted.
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  9. 9
    Vasoya, J. M.; Shah, A. V.; Serajuddin, A. T. M. Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of Ph. ADMET & DMPK. 2019, 7, 106– 130,  DOI: 10.5599/admet.661
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    There is no corresponding record for this reference.
  10. 10
    Kitak, T.; Dumičić, A.; Planinšek, O.; Šibanc, R.; Srčič, S. Determination of solubility parameters of ibuprofen and ibuprofen lysinate. Molecules 2015, 20, 21549– 21568,  DOI: 10.3390/molecules201219777
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    10
    Determination of solubility parameters of ibuprofen and ibuprofen lysinate
    Kitak, Teja; Dumicic, Aleksandra; Planinsek, Odon; Sibanc, Rok; Srcic, Stanko
    Molecules (2015), 20 (12), 21549-21568CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include soly. enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)soly. Here we focus on soly. parameters as a tool for predicting the soly. of a drug in certain carriers. Soly. parameters were detd. in two different ways: solely by using calcn. methods, and by exptl. approaches. Six different calcn. methods were applied in order to calc. the soly. parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calcn. models for salts are still not defined. Therefore, the extended Hansen's approach and inverse gas chromatog. (IGC) were used for evaluating of soly. parameters for ibuprofen lysinate. The obtained values of the total soly. parameter did not differ much between the two methods: by the extended Hansen's approach it was δt = 31.15 MPa0.5 and with IGC it was δt = 35.17 MPa0.5. However, the values of partial soly. parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behavior of a salt in the presence of various solvents.
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  11. 11
    Souto, E. B.; Müller, R. H. SLN and NLC for topical delivery of ketoconazole. J. Microencapsulation 2005, 22, 501– 510,  DOI: 10.1080/02652040500162436
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    11
    SLN and NLC for topical delivery of ketoconazole
    Souto, E. B.; Mueller, R. H.
    Journal of Microencapsulation (2005), 22 (5), 501-510CODEN: JOMIEF; ISSN:0265-2048. (Taylor & Francis Ltd.)
    The clin. use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aq. SLN and NLC dispersions, as well as the physicochem. stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepd. using Compritol 888 ATO as solid lipid. The natural antioxidant α-tocopherol was selected as liq. lipid compd. for the prepn. of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were phys. stable as suspensions during 3 mo of storage, but the SLN matrix was not able to protect the chem. labile ketoconazole against degrdn. under light exposure. In contrast, the NLC were able to stabilize the drug, but the aq. NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC phys. stabilized in a gel formulation.
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  12. 12
    Zadaliasghar, S.; Jouyban, A.; Martinez, F.; Barzegar-Jalali, M.; Rahimpour, E. Solubility of ketoconazole in the binary mixtures of 2-propanol and water at different temperatures. J. Mol. Liq. 2020, 300, 112259,  DOI: 10.1016/j.molliq.2019.112259
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    12
    Solubility of ketoconazole in the binary mixtures of 2-propanol and water at different temperatures
    Zadaliasghar, Samira; Jouyban, Abolghasem; Martinez, Fleming; Barzegar-Jalali, Mohammad; Rahimpour, Elaheh
    Journal of Molecular Liquids (2020), 300 (), 112259CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
    In the present study, the soly. of ketoconazole is measured by a shake - flask method in the binary solvent mixts. of 2-propanol + water at different temps. The exptl. soly. data are correlated/back-calcd. by some cosolvency models i.e. van't Hoff, Yalkowsky, Jouyban-Acree, Jouyban-Acree-van't Hoff, the mixt. response surface and the modified Wilson models. Moreover, the d. of ketoconazole satd. solns. is fitted by Jouyban-Acree model and the obtained equation is reported. The accuracy of these models is investigated by calcn. of the corresponding MRD%. The apparent thermodn. parameters including dissoln. std. enthalpy change (ΔHo), std. entropy change (ΔSo), Gibbs free energy change (ΔGo) for ketoconazole dissoln. are calcd. by using van't Hoff and Gibbs equations. Moreover, the preferential solvation anal. demonstrates that ketoconazole is preferentially solvated by water in water-rich and in 2-propanol-rich mixts., but preferentially solvated by 2-propanol in mixts. of compn. 0.19 < x1 < 0.58.
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  13. 13
    Mohammad, M. A.; Alhalaweh, A.; Velaga, S. P. Hansen solubility parameter as a tool to predict cocrystal formation. Int. J. Pharm. 2011, 407, 63– 71,  DOI: 10.1016/j.ijpharm.2011.01.030
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    13
    Hansen solubility parameter as a tool to predict cocrystal formation
    Mohammad, Mohammad Amin; Alhalaweh, Amjad; Velaga, Sitaram P.
    International Journal of Pharmaceutics (2011), 407 (1-2), 63-71CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen soly. parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calcd. according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calcd. using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the exptl. miscibility and cocrystal formation. The formation of cocrystals was also verified using liq.-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed exptl. as miscible. All tested theor. approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compd. types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using soly. parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.
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  14. 14
    Kalam, M. A.; Khan, A. A.; Alshamsan, A.; Haque, A.; Shakeel, F. Solubility of a poorly soluble immunosuppressant in different pure solvents: measurement, correlation, thermodynamics and molecular interactions. J. Mol. Liq. 2018, 249, 53– 60,  DOI: 10.1016/j.molliq.2017.11.028
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    There is no corresponding record for this reference.
  15. 15
    Alanazi, A.; Alshehri, S.; Altamimi, M.; Shakeel, F. Solubility determination and three dimensional Hansen solubility parameters of gefitinib in different organic solvents: Experimental and computational approaches. J. Mol. Liq. 2020, 299, 112211,  DOI: 10.1016/j.molliq.2019.112211
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    15
    Solubility determination and three dimensional Hansen solubility parameters of gefitinib in different organic solvents: Experimental and computational approaches
    Alanazi, Abdullah; Alshehri, Sultan; Altamimi, Mohammad; Shakeel, Faiyaz
    Journal of Molecular Liquids (2020), 299 (), 112211CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
    Gefitinib (GFT) is an anticancer drug which shows poor aq. soly. and bioavailability. The quant. soly. data of GFT in any aq., org. or the mixt. of aq. and org. solvents have not been reported in literature. Therefore, various exptl. and computational approaches for soly. detn. of GFT in different org. solvents were used in the proposed research. The soly. of GFT in various org. solvents namely "methanol, ethanol, isopropanol (IPA), 1-butanol, 2-butanol, ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), DMSO (DMSO) and Transcutol-HP (THP)" at "T = 298.2 K to 318.2 K" and "p = 0.1 MPa" was detd. using an isothermal satn. shake flask method. Exptl. solubilities of GFT were validated and correlated with "van't Hoff and Apelblat models". Various soly. parameters for GFT and different org. solvents were also detd. by "HSPiP software" in order to obtain the best solvents for GFT. Exptl. mole fraction solubilities of GFT were recorded highest in DMSO (3.50 x 10-2) followed by THP (3.28 x 10-2), PEG-400 (3.01 x 10-2), 2-butanol (4.62 x 10-3), 1-butanol (3.80 x 10-3), IPA (2.94 x 10-3), ethanol (2.07 x 10-3), PG (1.64 x 10-3), EG (1.44 x 10-3) and methanol (9.23 x 10-4) at "T = 318.2 K". Similar results were also obsd. at "T = 298.2 K, T = 303.2 K, T = 308.2 K and T = 313.2 K". Various soly. parameters of GFT were found to be closet with "DMSO, THP and PEG-400''. The results of activity coeffs. suggested max. solute-solvent interactions in "GFT-DMSO, GFT-THP and GFT-PEG-400''. Based on these results, "DMSO, THP and PEG-400'' were optimized as the best org. solvents for miscibility/soly. of GFT.
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  16. 16
    van-Krevelen, D.W.; te Nijenhuis, K. Properties of polymers: their correlation with chemical structure; their numerical estimation and prediction from additive group contributions; 4th edi.; Elsevier Science.: Amsterdam, The Netherland; Tokyo, Japan, 2009; pp. 223– 1031.
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    There is no corresponding record for this reference.
  17. 17
    Hancock, B. C.; York, P.; Rowe, R. C. The use of solubility parameters in pharmaceutical dosage form design. Int. J. Pharm. 1997, 148, 1– 21,  DOI: 10.1016/S0378-5173(96)04828-4
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    17
    The use of solubility parameters in pharmaceutical dosage form design
    Hancock, Bruno C.; York, Peter; Rowe, Raymond C.
    International Journal of Pharmaceutics (1997), 148 (1), 1-21CODEN: IJPHDE; ISSN:0378-5173. (Elsevier)
    A review with refs. The use and potential of soly. parameters for pharmaceutical dosage form design are reviewed in this paper. Specific ref. is given to the development of the approach, its previous usage and likely future applications. The advantages, assumptions and limitations of this type of approach are also described.
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  18. 18
    Grepioni, F.; Braga, D.; Chelazzi, L.; Shemchuk, O.; Maffei, P.; Sforzini, A.; Viscomi, G. C. Improving solubility and storage stability of rifaximin via solid-state solvation with Transcutol®. CrystEngComm 2019, 21, 5278– 5283,  DOI: 10.1039/C9CE00567F
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    18
    Improving solubility and storage stability of rifaximin via solid-state solvation with Transcutol
    Grepioni, F.; Braga, D.; Chelazzi, L.; Shemchuk, O.; Maffei, P.; Sforzini, A.; Viscomi, G. C.
    CrystEngComm (2019), 21 (35), 5278-5283CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    Crystn. of rifaximin from 2-(2-ethoxyethoxy)ethanol (Transcutol, DEGME or DEGEE), an inactive ingredient approved by the FDA and a solvent commonly used in the pharmaceutical and cosmetic fields, affords a cryst. form of the API with better soly. properties with respect to the known cryst. hydrates, which are characterized by a very low soly. in water and in buffered solns. The new form, named rifaximin t, is an anhyd. solvate, fully characterized by single crystal X-ray diffraction, differential scanning calorimetry (DSC) and thermogravimetric anal. (TGA). Soly. properties were also investigated and compared with known forms of rifaximin. Rifaximin t combines a high dissoln. rate, comparable to that of amorphous rifaximin, with a high storage stability, as in its solid form it is not affected by exposure to humidity.
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  19. 19
    Surov, A. O.; Voronin, A. P.; Manin, A. N.; Manin, N. G.; Kuzmina, L. G.; Churakov, A. V.; Perlovich, G. L. Pharmaceutical cocrystals of diflunisal and diclofenac with theophylline. Mol. Pharmaceutics 2014, 11, 3707– 3715,  DOI: 10.1021/mp5004652
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    19
    Pharmaceutical Cocrystals of Diflunisal and Diclofenac with Theophylline
    Surov, Artem O.; Voronin, Alexander P.; Manin, Alex N.; Manin, Nikolay G.; Kuzmina, Lyudmila G.; Churakov, Andrei V.; Perlovich, German L.
    Molecular Pharmaceutics (2014), 11 (10), 3707-3715CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Pharmaceutical cocrystals of nonsteroidal anti-inflammatory drugs diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) were obtained, and their crystal structures were detd. In both of the crystal structures, mols. form a hydrogen bonded supramol. unit consisting of a centrosym. dimer of THP and two mols. of active pharmaceutical ingredient (API). Crystal lattice energy calcns. showed that the packing energy gain of the [DIC + THP] cocrystal is derived mainly from the dispersion energy, which dominates the structures of the cocrystals. The enthalpies of cocrystal formation were estd. by soln. calorimetry, and their thermal stability was studied by differential scanning calorimetry. The cocrystals showed an enhancement of apparent soly. compared to the corresponding pure APIs, while the intrinsic dissoln. rates are comparable. Both cocrystals demonstrated phys. stability upon storing at different relative humidity.
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  20. 20
    Etman, M. A.; Naggar, V. F. Thermodynamics of paracetamol solubility in sugar-water cosolvent systems. Int. J. Pharm. 1999, 58, 177– 184,  DOI: 10.1016/0378-5173(90)90193-8
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    There is no corresponding record for this reference.
  21. 21
    Jouyban, A.; Acree, W. E., Jr.; Martínez, F. Dissolution thermodynamics and preferential solvation of ketoconazole in some {ethanol (1) + water (2)} mixtures. J. Mol. Liq. 2020, 313, 113579,  DOI: 10.1016/j.molliq.2020.113579
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    21
    Dissolution thermodynamics and preferential solvation of ketoconazole in some {ethanol (1) + water (2)} mixtures
    Jouyban, Abolghasem; Acree, William E. Jr.; Martinez, Fleming
    Journal of Molecular Liquids (2020), 313 (), 113579CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
    In this research, the equil. mole fraction soly. of ketoconazole in some aq.-ethanolic mixts. was calcd. from previously measured soly. data reported in molarity scale at temps. from 298.2 to 313.2 K. Exptl. mole fraction soly. values were adequately correlated with the Jouyban-Acree and Jouyban-Acree-van't Hoff models. The resp. apparent thermodn. functions (Gibbs energy, enthalpy, and entropy of the dissoln. processes) were computed using the van't Hoff and Gibbs equations. The enthalpy-entropy relationship for ketoconazole was non-linear in the plot of enthalpy vs. Gibbs energy of soln. with neg. slope in the compn. region 0.00 ≤ w1 ≤ 0.20 but pos. slope in the region 0.20 ≤ w1 ≤ 0.70. Beyond this compn., the behavior is more complex. In addn., the inverse Kirkwood-Buff integrals were used to investigate the preferential solvation of ketoconazole which is preferentially solvated by water mols. in water-rich and also in ethanol-rich mixts. but preferentially solvated by ethanol mols. in mixts. 0.24 ≤ x1 ≤ 0.75. Dissoln. thermodn. and preferential solvation computations were carried out employing whole exptl. soly. data points and the simulated data using a min. no. of seven data points as training set, in which there were no significant differences in the obtained numerical values except for enthalpy-entropy compensation data.
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  22. 22
    Jahromi, R.; Mogharab, V.; Jahromi, H.; Avazpour, A. Synergistic effects of anionic surfactants on coronavirus (SARS-CoV-2) virucidal efficiency of sanitizing fluids to fight COVID-19. Food Chem. Toxicol. 2020, 145, 111702,  DOI: 10.1016/j.fct.2020.111702
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    22
    Synergistic effects of anionic surfactants on coronavirus (SARS-CoV-2) virucidal efficiency of sanitizing fluids to fight COVID-19
    Jahromi, Reza; Mogharab, Vahid; Jahromi, Hossein; Avazpour, Arezoo
    Food and Chemical Toxicology (2020), 145 (), 111702CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
    Our surrounding environment, esp. often-touched contaminated surfaces, plays an important role in the transmission of pathogens in society. The shortage of effective sanitizing fluids, however, became a global challenge quickly after the coronavirus disease-19 (COVID-19) outbreak in Dec. 2019. In this study, we present the effect of surfactants on coronavirus (SARS-CoV-2) virucidal efficiency in sanitizing fluids. Sodium dodecylbenzenesulfonate (SDBS), sodium laureth sulfate (SLS), and two com. dish soap and liq. hand soap were studied with the goal of evapn. rate redn. in sanitizing liqs. to maximize surface contact time. Twelve fluids with different recipes composed of ethanol, isopropanol, SDBS, SLS, glycerin, and water of standardized hardness (WSH) were tested for their evapn. time and virucidal efficiency. Evapn. time increased by 17-63% when surfactant agents were added to the liq. In addn., surfactant incorporation enhanced the virucidal efficiency between 15 and 27% according to the 4-field test in the EN 16615:2015 European Std. method. Most importantly, however, we found that surfactant addn. provides a synergistic effect with alcs. to inactivate the SARS-CoV-2 virus. This study provides a simple, yet effective soln. to improve the virucidal efficiency of commonly used sanitizers.
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  23. 23
    Osborne, D. W.; Musakhanian, J. Skin Penetration and Permeation Properties of Transcutol®-Neat or Diluted Mixtures. AAPS PharmSciTech 2018, 19, 3512– 3533,  DOI: 10.1208/s12249-018-1196-8
    Google Scholar
    23
    Skin Penetration and Permeation Properties of Transcutol-Neat or Diluted Mixtures
    Osborne, David W.; Musakhanian, Jasmine
    AAPS PharmSciTech (2018), 19 (8), 3512-3533CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
    A review. A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by phys. means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) com. known as Transcutol. Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol. In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to exptl. variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol influences skin penetration and permeation. [Figure not available: see fulltext.].
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFyhtL%252FN&md5=b59ab89eec155f3f757c50a82d966b0e
  24. 24
    Roy, C.; Charkrabarty, J. Stability indicating validated novel RP-HPLC method for simulataneous estimation of methylparaben, ketoconazole and mometasone furoate in topical pharmaceutical dosage formulation. ISRN Anal. Chem. 2013, 1,  DOI: 10.1155/2013/342794
    Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Harris, R.; Jones, H. E.; Artis, W. M. Orally Administered Ketoconazole: Route of Delivery to the Human Stratum Corneum. Antimicrob. Agents Chemother. 1983, 876– 882,  DOI: 10.1128/AAC.24.6.876
    Google Scholar
    25
    Orally administered ketoconazole: route of delivery to the human stratum corneum
    Harris, Russell; Jones, Henry E.; Artis, William M.
    Antimicrobial Agents and Chemotherapy (1983), 24 (6), 876-82CODEN: AMACCQ; ISSN:0066-4804.
    Healthy volunteers, patients with chronic fungal disease, and a patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole (I) [65277-42-1] daily for various lengths of time. Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 μg ketoconazole/g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from patients with chronic fungal infection treated for >9 mo contained ketoconazole (4.7 μg/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 μg/mL on day 7 and 0.084 μg/mL on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole contg. eccrine sweat demonstrated a 10-fold greater concn. in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. Thus, eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids.
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  26. 26
    Hildebrand, J. H.; Scott, R. L. Regular solutions; Prentice-Hall: Saddle River, NJ, USA, 1962; pp. 202.
    Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Hildebrand, J. H.; Scott, R. L. The solubility of nonelectrolytes; Reinhold Pub. Corp.: New York, NY, USA, 1950; pp. 514.
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Hansen, C. M. Hansen solubility parameters: A User’s Handbook; 2nd ed.; CRC Press: Boca Raton, FL, USA, 2007; pp. 544.
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Ruidiaz, M. A.; Delgado, D. R.; Martínez, F.; Marcus, Y. Solubility and preferential solvation of indomethacin in 1,4-dioxane + water solvent mixtures. Fluid Phase Equilib. 2010, 299, 259– 265,  DOI: 10.1016/j.fluid.2010.09.027
    Google Scholar
    29
    Solubility and preferential solvation of indomethacin in 1,4-dioxane + water solvent mixtures
    Ruidiaz, Miller A.; Delgado, Daniel R.; Martinez, Fleming; Marcus, Yizhak
    Fluid Phase Equilibria (2010), 299 (2), 259-265CODEN: FPEQDT; ISSN:0378-3812. (Elsevier B.V.)
    The solubilities of indomethacin (IMC) in 1,4-dioxane + water cosolvent mixts. were detd. at several temps., 293.15-313.15 K. The thermodn. functions: Gibbs energy, enthalpy, and entropy of soln. and of mixing were obtained from these data by using the van't Hoff and Gibbs equations. The soly. was maximal in 0.95 mass fraction of 1,4-dioxane and very low in pure water at all the temps. A non-linear plot of ΔHsoln° vs. ΔGsoln° with neg. slope from pure water up to 0.60 mass fraction of 1,4-dioxane and pos. beyond this up to 0.95 mass fraction of 1,4-dioxane was obtained. Accordingly, the driving mechanism for IMC soly. in water-rich mixts. is the entropy, probably due to water-structure loss around the drug non-polar moieties by 1,4-dioxane, whereas, above 0.60 mass fraction of 1,4-dioxane the driving mechanism is the enthalpy, probably due to IMC solvation increase by the co-solvent mols. The preferential solvation of IMC by the components of the solvent was estd. by means of the quasi-lattice quasi-chem. method, whereas the inverse Kirkwood-Buff integral method could not be applied because of divergence of the integrals in intermediate compns.
    >> More from SciFinder ®
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  30. 30
    Williams, R. O. B. Solubility and Solubilization in Aqueous Media By Samuel H. Yalkowsky (University of Arizona). Oxford University Press: New York. 1999. xvi + 464 pp. $165. ISBN 0-8412-3576-7. J. Am. Chem. Soc. 2000, 122, 9882,  DOI: 10.1021/ja0047424
    Google Scholar
    30
    Solubility and Solubilization in Aqueous Media. By Samuel H. Yalkowsky (University of Arizona). Oxford University Press: New York. 1999. xvi + 464 pp. $165. ISBN 0-8412-3576-7.
    Williams, Robert O., III
    Journal of the American Chemical Society (2000), 122 (40), 9882CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlsVensbg%253D&md5=2b6a1e51a8a69eb7ca3e6bd34ac675f4
  31. 31
    Apelblat, A.; Manzurola, E. Solubilities ofo-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic andp-toluic acid and magnesium-DL-aspartate in water from T = 20 (278–348) K. J. Chem. Thermodyn. 1999, 31, 85– 91,  DOI: 10.1006/jcht.1998.0424
    Google Scholar
    31
    Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water from T=(278 to 348) K
    Apelblat, Alexander; Manzurola, Emanuel
    Journal of Chemical Thermodynamics (1999), 31 (1), 85-91CODEN: JCTDAF; ISSN:0021-9614. (Academic Press)
    Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water were detd. in the temp. range (278 to 345) K. The apparent molar enthalpies of soln. at T=298.15 K were derived from these solubilities, and the resulting values are ΔsolHm(o-C9H8O4, m=0.0226 mol·kg-1)=22.9 kJ·mol-1, ΔsolHm(4-C7H7O3N, m=0.00758 mol·kg-1)=26.1 kJ·mol-1, ΔsolHm(3,5-C7H4O7N2, m=0.0633 mol·kg-1)=28.7 kJ·mol-1, ΔsolHm(p-C8H8O2, m=0.00258 mol·kg-1)=24.0 kJ·mol-1, and ΔsolHm(dl-C8H12O3N2Mg, m=0.1485 mol·kg-1)=11.7 kJ·mol-1. (c) 1999 Academic Press.
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  32. 32
    Manzurola, E.; Apelblat, A. Solubilities of L-glutamic acid, 3-nitrobenzoic acid, acetylsalicylic, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL- aspartate, and magnesium-L-lactate in water. J. Chem. Thermodyn. 2002, 34, 1127– 1136,  DOI: 10.1006/jcht.2002.0975
    Google Scholar
    32
    Solubilities of L-glutamic acid, 3-nitrobenzoic acid, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL-aspartate, and magnesium-L-lactate in water
    Manzurola, Emanuel; Apelblat, Alexander
    Journal of Chemical Thermodynamics (2002), 34 (7), 1127-1136CODEN: JCTDAF; ISSN:0021-9614. (Elsevier Science Ltd.)
    Solubilities of L-glutamic acid, 3-nitrobenzoic acid, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL-aspartate, and magnesium-L-lactate in water were detd. in the temp. range 278 to 343 K. The apparent molar enthalpies of soln. at T = 298.15 K as derived from these solubilities are ΔsolHm(L-glutamic acid, msat = 0.0565 mol·kg-1) = 30.2 kJ·mol-1, ΔsolHm(3-nitrobenzoic acid, m =0.0188 mol·kg-1) = 28.1 kJ·mol-1, ΔsolHm(p-toluic acid, m = 0.00267 mol·kg-1) = 23.9 kJ·mol-1, ΔsolHm(calcium-L-lactate tetrahydrate, m = 0.2902 mol·kg-1) = 25.8 kJ·mol-1, ΔsolHm(calcium gluconate, m = 0.0806 mol·kg-1) = 22.1 kJ·mol-1, ΔsolHm(magnesium-DL-aspartate tetrahydrate, m = 0.1469 mol·kg-1) = 11.5 kJ·mol-1, and ΔsolHm(magnesium-L-lactate trihydrate, m = 0.3462 mol·kg-1) = 3.81 kJ·mol-1.
    >> More from SciFinder ®
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  33. 33
    Krug, R. R.; Hunter, W. G.; Grieger, R. A. Enthalpy-entropy compensation. 2. Separation of the chemical from the statistic effect. J. Phys. Chem. 1976, 80, 2341– 2351,  DOI: 10.1021/j100562a007
    Google Scholar
    33
    Enthalpy-entropy compensation. 2. Separation of the chemical from the statistical effect
    Krug, R. R.; Hunter, W. G.; Grieger, R. A.
    Journal of Physical Chemistry (1976), 80 (21), 2341-51CODEN: JPCHAX; ISSN:0022-3654.
    For problems concerning enthalpy-entropy compensations, an appropriate regression procedure is presented for the estn. of functional dependencies between thermodn. parameters. Unbiased parameter ests. and their confidence intervals are derived for the case of a linear dependence between thermodn. parameters. It is demonstrated that nonlinear as well as linear functional dependencies are readily detectable when enthalpy ests. are plotted vs. free energy ests. Some linear and nonlinear examples of functional dependencies between thermodn. parameters are analyzed and discussed.
    >> More from SciFinder ®
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  • Abstract

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    Figure 1

    Figure 1. (A) Chemical structure of ketoconazole, (B) DSC thermogram of pure and equilibrated ketoconazole (recovered from methanol), and (C) chromatogram of pure ketoconazole with a retention time of 6.789 min from method validation (Empower 2 software)

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    Figure 2

    Figure 2. Correlation of lnxe values of ketoconazole with the Apelblat model in various organic solvents as a function of 1/T.

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    Figure 3

    Figure 3. van’t Hoff plot for ketoconazole plotted between lnxe and (1/T – 1/Thm) for the drug in various organic solvents.

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    Figure 4

    Figure 4. GastroPlus-based simulation and prediction study: (A) In vitro drug release behavior and Weibull model distribution of neat ketoconazole suspension (blue line for sigmoidal release pattern), (B) in vitro drug release behavior and Weibull model distribution of THP solubilized ketoconazole (blue line for sigmoidal release pattern) in buffer solution (pH 7.4), (C) skin absorption of neat ketoconazole from suspension, and (D) skin absorption of THP-solubilized ketoconazole.

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    Figure 5

    Figure 5. GastroPlus-based prediction of a relationship between dissolution and skin permeation of ketoconazole dissolved in THP. The inset of the figure predicted the plasma concentration time profile of THP solubilized ketoconazole when administeresd orally (0.1 mg).

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  • References

    This article references 33 other publications.

    1. 1
      Bongomin, F.; Gago, S.; Oladele, R.; Denning, D. Global and multi-national pre-valence of fungal diseases—estimate precision. J. Fungi 2017, 3, 57,  DOI: 10.3390/jof3040057
      There is no corresponding record for this reference.
    2. 2
      Hashemzadeh, N.; Jouyban, A. Solubility of Ketoconazole in Ethanol + Water Mixtures at Various Temperatures. Chem. Eng. Commun. 2015, 202, 1211– 1215,  DOI: 10.1080/00986445.2014.912636
      2
      Solubility of Ketoconazole in Ethanol + Water Mixtures at Various Temperatures
      Hashemzadeh, Nastaran; Jouyban, Abolghasem
      Chemical Engineering Communications (2015), 202 (9), 1211-1215CODEN: CEGCAK; ISSN:0098-6445. (Taylor & Francis, Inc.)
      Ketoconazole is an important drug with low water soly. Its low aq. soly. could be increased using various methods such as by the addn. of a pharmaceutical cosolvent. The soly. of ketoconazole in ethanol + water mixts. at 293.2, 298.2, 303.2, and 308.2 K were detd., and the addn. of ethanol increased the soly. and the max. value was obtained at 80% of ethanol. The generated data were math. represented using the Jouyban-Acree model within an acceptable accuracy.
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    3. 3
      Jacobs, G. A.; Gerber, M.; Malan, M. M.; du Preez, J. L.; Fox, L. T.; du Plessis, J. Topical delivery of acyclovir and ketoconazole. Drug Delivery 2016, 23, 631– 641,  DOI: 10.3109/10717544.2014.933283
      3
      Topical delivery of acyclovir and ketoconazole
      Jacobs, Gerda A.; Gerber, Minja; Malan, Maides M.; du Preez, Jan L.; Fox, Lizelle T.; du Plessis, Jeanetta
      Drug Delivery (2016), 23 (2), 631-641CODEN: DDELEB; ISSN:1071-7544. (Taylor & Francis Ltd.)
      Context: Viral and fungal cutaneous manifestations are regularly encountered in immunocompromised human immunodeficiency virus/acquired immunodeficiency syndrome individuals and can be treated by drugs such as acyclovir and ketoconazole, resp. Objective: The aim of this study was to det. whether the novel Pheroid delivery system improved the transdermal delivery and/or dermal delivery of acyclovir and ketoconazole when incorporated into semi-solid formulations. Materials and methods: Semi-solid products (creams and emulgels) contg. these drug compds. were formulated, either with or without (control) the Pheroid delivery system. The stability of the formulated semi-solid products was examd. over a period of six months and included the assay of the actives, pH, viscosity, mass loss and particle size observation. Vertical Franz cell diffusion studies and tape stripping methods were used to det. the in vitro, stratum corneum (SC)-epidermis and epidermis-dermis delivery of these formulations. Results and discussion: Stability tests showed that none of the formulations were completely stable. Acyclovir showed a biphasic character during the in vitro skin diffusion studies for all the tested formulations. The Pheroid cream enhanced the transdermal, SC-epidermis and epidermis-dermis delivery of acyclovir the most. The av. amt. of ketoconazole diffused over 12 h showed improved delivery of ketoconazole, with the Pheroid emulgel exhibiting the best transdermal and epidermis-dermis delivery. Conclusion: The Pheroid formulas increased transdermal penetration as well as delivery to the dermal and epidermal skin layers. The Pheroid emulgel and the Pheroid cream increased the topical delivery of ketoconazole and acyclovir, resp.
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    4. 4
      Durden, F. M.; Elewski, B. Fungal infections in HIV-infected patients. Semin. Cutaneous Med. Surg. 1997, 16, 200– 212,  DOI: 10.1016/S1085-5629(97)80043-0
      4
      Fungal infections in HIV-infected patients
      Durden F M; Elewski B
      Seminars in cutaneous medicine and surgery (1997), 16 (3), 200-12 ISSN:1085-5629.
      Opportunistic fungal infections are commonly encountered in the acquired immunodeficiency syndrome (AIDS) patient population. Fungal infections in the patient infected with the human immunodeficiency virus (HIV) are a major cause of morbidity and mortality. The yeasts Candida and Cryptococcus neoformans, the dimorphic fungi Histoplasma capsulatum and Sporothrix schenckii, and the dermatophyte fungi are the most common pathogenic fungi in patients infected with HIV. The characteristics of these and other relevant mycotic pathogens, and their clinical presentation are discussed. Mycoses in the patient infected with HIV are often atypical, and can be masked by other infections. Cutaneous manifestations may provide valuable diagnostic clues. The clinician must maintain a high index of suspicion to establish an early diagnosis and rapidly institute therapy. Treatment may suppress rather than cure the mycosis, because host immunity in conjunction with antifungal agents is necessary to eliminate infection.
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    5. 5
      Hossin, B.; Rizi, K.; Murdan, S. Application of Hansen Solubility Parameters to predict drug–nail interactions, which can assist the design of nail medicines. Eur. J. Pharm. Biopharm. 2016, 102, 32– 40,  DOI: 10.1016/j.ejpb.2016.02.009
      5
      Application of Hansen Solubility Parameters to predict drug-nail interactions, which can assist the design of nail medicines
      Hossin, B.; Rizi, K.; Murdan, S.
      European Journal of Pharmaceutics and Biopharmaceutics (2016), 102 (), 32-40CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      We hypothesised that Hansen Soly. Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) det. the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/soly. in org. liqs., (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of exptl.-detd. affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match exptl. reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Soly. Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.
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    6. 6
      Jouyban, A.; Soleymani, J.; Soltanpour, S. Solubility of Ketoconazole in Polyethylene Glycol 200 + Water Mixtures at 298.2–318.2 K. J. Solution Chem. 2014, 43, 950– 958,  DOI: 10.1007/s10953-014-0171-6
      6
      Solubility of ketoconazole in polyethylene glycol 200 + water mixtures at 298.2-318.2 K
      Jouyban, Abolghasem; Soleymani, Jafar; Soltanpour, Shahla
      Journal of Solution Chemistry (2014), 43 (5), 950-958CODEN: JSLCAG; ISSN:0095-9782. (Springer)
      The soly. of ketoconazole in binary mixts. of polyethylene glycol 200 (PEG 200) + water is reported at temps. ranging from 298.2 to 318.2 K. The Jouyban-Acree model and its combined version including the van't Hoff equation were used for correlating the reported data; the obtained mean relative deviations are 9.5 and 9.9 %, resp. Also, two previously trained versions of the Jouyban-Acree model were used for predicting the reported data points in which the prediction errors were 34.6 and 31.0%.
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    7. 7
      Soltanpour, S.; Nazemi, V. Solubility of Ketoconazole in Binary and Ternary Solvents of Polyethylene Glycols 200, 400 or 600 with Ethanol and Water at 298.2 K. Data Report and Analysis. J. Solution Chem. 2018, 47, 65– 79,  DOI: 10.1007/s10953-017-0708-6
      7
      Solubility of Ketoconazole in Binary and Ternary Solvents of Polyethylene Glycols 200, 400 or 600 with Ethanol and Water at 298.2 K. Data Report and Analysis
      Soltanpour, Shahla; Nazemi, Vahideh
      Journal of Solution Chemistry (2018), 47 (1), 65-79CODEN: JSLCAG; ISSN:0095-9782. (Springer)
      The solubilities of ketoconazole in binary and ternary mixts. of water, ethanol and polyethylene glycols 200, 400 or 600 (185 data points) were detd. at 298.2 K. Williams-Amidon and Jouyban-Acree cosolvency models were used to model the data, with overall mean relative deviations (OMRDs) for the soly. data in binary and ternary solvents of 17.5 and 23.5%, resp. For predicting the soly. data of ketoconazole the trained versions of the models were used and the OMRD values were 47.7 and 33.0%, resp.
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    8. 8
      Lane, M. E. Skin penetration enhancers. Int. J. Pharm. 2013, 447, 12– 21,  DOI: 10.1016/j.ijpharm.2013.02.040
      8
      Skin penetration enhancers
      Lane, Majella E.
      International Journal of Pharmaceutics (Amsterdam, Netherlands) (2013), 447 (1-2), 12-21CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      A review. The skin has evolved to prevent excessive water loss from the internal organs and to limit the ability of xenobiotics and hazardous substances to enter the body. Notwithstanding this barrier function, a no. of strategies have been developed by scientists to deliver drugs to and through the skin. The aim of this review is to consider the various types of chem. penetration enhancers (CPEs) which have been investigated in the scientific literature. Potential pathways for CPEs to exert their action are examd. with ref. to the phys. chem. of passive skin transport. The emphasis is on those studies which have focussed on human and porcine skin because of the limitations assocd. with skin permeation data collated from other species. Where known, the mechanisms of action of these compds. are also discussed. Examples of enhancers used in com. topical and transdermal formulations are provided. It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a Diffusion-Partition-Soly. theory. Finally, some of the limitations of studies in the literature are considered and the importance of monitoring the fate of the penetration enhancer as well as the active is highlighted.
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    9. 9
      Vasoya, J. M.; Shah, A. V.; Serajuddin, A. T. M. Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of Ph. ADMET & DMPK. 2019, 7, 106– 130,  DOI: 10.5599/admet.661
      There is no corresponding record for this reference.
    10. 10
      Kitak, T.; Dumičić, A.; Planinšek, O.; Šibanc, R.; Srčič, S. Determination of solubility parameters of ibuprofen and ibuprofen lysinate. Molecules 2015, 20, 21549– 21568,  DOI: 10.3390/molecules201219777
      10
      Determination of solubility parameters of ibuprofen and ibuprofen lysinate
      Kitak, Teja; Dumicic, Aleksandra; Planinsek, Odon; Sibanc, Rok; Srcic, Stanko
      Molecules (2015), 20 (12), 21549-21568CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include soly. enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)soly. Here we focus on soly. parameters as a tool for predicting the soly. of a drug in certain carriers. Soly. parameters were detd. in two different ways: solely by using calcn. methods, and by exptl. approaches. Six different calcn. methods were applied in order to calc. the soly. parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calcn. models for salts are still not defined. Therefore, the extended Hansen's approach and inverse gas chromatog. (IGC) were used for evaluating of soly. parameters for ibuprofen lysinate. The obtained values of the total soly. parameter did not differ much between the two methods: by the extended Hansen's approach it was δt = 31.15 MPa0.5 and with IGC it was δt = 35.17 MPa0.5. However, the values of partial soly. parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behavior of a salt in the presence of various solvents.
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    11. 11
      Souto, E. B.; Müller, R. H. SLN and NLC for topical delivery of ketoconazole. J. Microencapsulation 2005, 22, 501– 510,  DOI: 10.1080/02652040500162436
      11
      SLN and NLC for topical delivery of ketoconazole
      Souto, E. B.; Mueller, R. H.
      Journal of Microencapsulation (2005), 22 (5), 501-510CODEN: JOMIEF; ISSN:0265-2048. (Taylor & Francis Ltd.)
      The clin. use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aq. SLN and NLC dispersions, as well as the physicochem. stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepd. using Compritol 888 ATO as solid lipid. The natural antioxidant α-tocopherol was selected as liq. lipid compd. for the prepn. of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were phys. stable as suspensions during 3 mo of storage, but the SLN matrix was not able to protect the chem. labile ketoconazole against degrdn. under light exposure. In contrast, the NLC were able to stabilize the drug, but the aq. NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC phys. stabilized in a gel formulation.
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    12. 12
      Zadaliasghar, S.; Jouyban, A.; Martinez, F.; Barzegar-Jalali, M.; Rahimpour, E. Solubility of ketoconazole in the binary mixtures of 2-propanol and water at different temperatures. J. Mol. Liq. 2020, 300, 112259,  DOI: 10.1016/j.molliq.2019.112259
      12
      Solubility of ketoconazole in the binary mixtures of 2-propanol and water at different temperatures
      Zadaliasghar, Samira; Jouyban, Abolghasem; Martinez, Fleming; Barzegar-Jalali, Mohammad; Rahimpour, Elaheh
      Journal of Molecular Liquids (2020), 300 (), 112259CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
      In the present study, the soly. of ketoconazole is measured by a shake - flask method in the binary solvent mixts. of 2-propanol + water at different temps. The exptl. soly. data are correlated/back-calcd. by some cosolvency models i.e. van't Hoff, Yalkowsky, Jouyban-Acree, Jouyban-Acree-van't Hoff, the mixt. response surface and the modified Wilson models. Moreover, the d. of ketoconazole satd. solns. is fitted by Jouyban-Acree model and the obtained equation is reported. The accuracy of these models is investigated by calcn. of the corresponding MRD%. The apparent thermodn. parameters including dissoln. std. enthalpy change (ΔHo), std. entropy change (ΔSo), Gibbs free energy change (ΔGo) for ketoconazole dissoln. are calcd. by using van't Hoff and Gibbs equations. Moreover, the preferential solvation anal. demonstrates that ketoconazole is preferentially solvated by water in water-rich and in 2-propanol-rich mixts., but preferentially solvated by 2-propanol in mixts. of compn. 0.19 < x1 < 0.58.
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    13. 13
      Mohammad, M. A.; Alhalaweh, A.; Velaga, S. P. Hansen solubility parameter as a tool to predict cocrystal formation. Int. J. Pharm. 2011, 407, 63– 71,  DOI: 10.1016/j.ijpharm.2011.01.030
      13
      Hansen solubility parameter as a tool to predict cocrystal formation
      Mohammad, Mohammad Amin; Alhalaweh, Amjad; Velaga, Sitaram P.
      International Journal of Pharmaceutics (2011), 407 (1-2), 63-71CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen soly. parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calcd. according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calcd. using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the exptl. miscibility and cocrystal formation. The formation of cocrystals was also verified using liq.-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed exptl. as miscible. All tested theor. approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compd. types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using soly. parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.
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    14. 14
      Kalam, M. A.; Khan, A. A.; Alshamsan, A.; Haque, A.; Shakeel, F. Solubility of a poorly soluble immunosuppressant in different pure solvents: measurement, correlation, thermodynamics and molecular interactions. J. Mol. Liq. 2018, 249, 53– 60,  DOI: 10.1016/j.molliq.2017.11.028
      There is no corresponding record for this reference.
    15. 15
      Alanazi, A.; Alshehri, S.; Altamimi, M.; Shakeel, F. Solubility determination and three dimensional Hansen solubility parameters of gefitinib in different organic solvents: Experimental and computational approaches. J. Mol. Liq. 2020, 299, 112211,  DOI: 10.1016/j.molliq.2019.112211
      15
      Solubility determination and three dimensional Hansen solubility parameters of gefitinib in different organic solvents: Experimental and computational approaches
      Alanazi, Abdullah; Alshehri, Sultan; Altamimi, Mohammad; Shakeel, Faiyaz
      Journal of Molecular Liquids (2020), 299 (), 112211CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
      Gefitinib (GFT) is an anticancer drug which shows poor aq. soly. and bioavailability. The quant. soly. data of GFT in any aq., org. or the mixt. of aq. and org. solvents have not been reported in literature. Therefore, various exptl. and computational approaches for soly. detn. of GFT in different org. solvents were used in the proposed research. The soly. of GFT in various org. solvents namely "methanol, ethanol, isopropanol (IPA), 1-butanol, 2-butanol, ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), DMSO (DMSO) and Transcutol-HP (THP)" at "T = 298.2 K to 318.2 K" and "p = 0.1 MPa" was detd. using an isothermal satn. shake flask method. Exptl. solubilities of GFT were validated and correlated with "van't Hoff and Apelblat models". Various soly. parameters for GFT and different org. solvents were also detd. by "HSPiP software" in order to obtain the best solvents for GFT. Exptl. mole fraction solubilities of GFT were recorded highest in DMSO (3.50 x 10-2) followed by THP (3.28 x 10-2), PEG-400 (3.01 x 10-2), 2-butanol (4.62 x 10-3), 1-butanol (3.80 x 10-3), IPA (2.94 x 10-3), ethanol (2.07 x 10-3), PG (1.64 x 10-3), EG (1.44 x 10-3) and methanol (9.23 x 10-4) at "T = 318.2 K". Similar results were also obsd. at "T = 298.2 K, T = 303.2 K, T = 308.2 K and T = 313.2 K". Various soly. parameters of GFT were found to be closet with "DMSO, THP and PEG-400''. The results of activity coeffs. suggested max. solute-solvent interactions in "GFT-DMSO, GFT-THP and GFT-PEG-400''. Based on these results, "DMSO, THP and PEG-400'' were optimized as the best org. solvents for miscibility/soly. of GFT.
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    16. 16
      van-Krevelen, D.W.; te Nijenhuis, K. Properties of polymers: their correlation with chemical structure; their numerical estimation and prediction from additive group contributions; 4th edi.; Elsevier Science.: Amsterdam, The Netherland; Tokyo, Japan, 2009; pp. 223– 1031.
      There is no corresponding record for this reference.
    17. 17
      Hancock, B. C.; York, P.; Rowe, R. C. The use of solubility parameters in pharmaceutical dosage form design. Int. J. Pharm. 1997, 148, 1– 21,  DOI: 10.1016/S0378-5173(96)04828-4
      17
      The use of solubility parameters in pharmaceutical dosage form design
      Hancock, Bruno C.; York, Peter; Rowe, Raymond C.
      International Journal of Pharmaceutics (1997), 148 (1), 1-21CODEN: IJPHDE; ISSN:0378-5173. (Elsevier)
      A review with refs. The use and potential of soly. parameters for pharmaceutical dosage form design are reviewed in this paper. Specific ref. is given to the development of the approach, its previous usage and likely future applications. The advantages, assumptions and limitations of this type of approach are also described.
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    18. 18
      Grepioni, F.; Braga, D.; Chelazzi, L.; Shemchuk, O.; Maffei, P.; Sforzini, A.; Viscomi, G. C. Improving solubility and storage stability of rifaximin via solid-state solvation with Transcutol®. CrystEngComm 2019, 21, 5278– 5283,  DOI: 10.1039/C9CE00567F
      18
      Improving solubility and storage stability of rifaximin via solid-state solvation with Transcutol
      Grepioni, F.; Braga, D.; Chelazzi, L.; Shemchuk, O.; Maffei, P.; Sforzini, A.; Viscomi, G. C.
      CrystEngComm (2019), 21 (35), 5278-5283CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      Crystn. of rifaximin from 2-(2-ethoxyethoxy)ethanol (Transcutol, DEGME or DEGEE), an inactive ingredient approved by the FDA and a solvent commonly used in the pharmaceutical and cosmetic fields, affords a cryst. form of the API with better soly. properties with respect to the known cryst. hydrates, which are characterized by a very low soly. in water and in buffered solns. The new form, named rifaximin t, is an anhyd. solvate, fully characterized by single crystal X-ray diffraction, differential scanning calorimetry (DSC) and thermogravimetric anal. (TGA). Soly. properties were also investigated and compared with known forms of rifaximin. Rifaximin t combines a high dissoln. rate, comparable to that of amorphous rifaximin, with a high storage stability, as in its solid form it is not affected by exposure to humidity.
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    19. 19
      Surov, A. O.; Voronin, A. P.; Manin, A. N.; Manin, N. G.; Kuzmina, L. G.; Churakov, A. V.; Perlovich, G. L. Pharmaceutical cocrystals of diflunisal and diclofenac with theophylline. Mol. Pharmaceutics 2014, 11, 3707– 3715,  DOI: 10.1021/mp5004652
      19
      Pharmaceutical Cocrystals of Diflunisal and Diclofenac with Theophylline
      Surov, Artem O.; Voronin, Alexander P.; Manin, Alex N.; Manin, Nikolay G.; Kuzmina, Lyudmila G.; Churakov, Andrei V.; Perlovich, German L.
      Molecular Pharmaceutics (2014), 11 (10), 3707-3715CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Pharmaceutical cocrystals of nonsteroidal anti-inflammatory drugs diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) were obtained, and their crystal structures were detd. In both of the crystal structures, mols. form a hydrogen bonded supramol. unit consisting of a centrosym. dimer of THP and two mols. of active pharmaceutical ingredient (API). Crystal lattice energy calcns. showed that the packing energy gain of the [DIC + THP] cocrystal is derived mainly from the dispersion energy, which dominates the structures of the cocrystals. The enthalpies of cocrystal formation were estd. by soln. calorimetry, and their thermal stability was studied by differential scanning calorimetry. The cocrystals showed an enhancement of apparent soly. compared to the corresponding pure APIs, while the intrinsic dissoln. rates are comparable. Both cocrystals demonstrated phys. stability upon storing at different relative humidity.
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    20. 20
      Etman, M. A.; Naggar, V. F. Thermodynamics of paracetamol solubility in sugar-water cosolvent systems. Int. J. Pharm. 1999, 58, 177– 184,  DOI: 10.1016/0378-5173(90)90193-8
      There is no corresponding record for this reference.
    21. 21
      Jouyban, A.; Acree, W. E., Jr.; Martínez, F. Dissolution thermodynamics and preferential solvation of ketoconazole in some {ethanol (1) + water (2)} mixtures. J. Mol. Liq. 2020, 313, 113579,  DOI: 10.1016/j.molliq.2020.113579
      21
      Dissolution thermodynamics and preferential solvation of ketoconazole in some {ethanol (1) + water (2)} mixtures
      Jouyban, Abolghasem; Acree, William E. Jr.; Martinez, Fleming
      Journal of Molecular Liquids (2020), 313 (), 113579CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
      In this research, the equil. mole fraction soly. of ketoconazole in some aq.-ethanolic mixts. was calcd. from previously measured soly. data reported in molarity scale at temps. from 298.2 to 313.2 K. Exptl. mole fraction soly. values were adequately correlated with the Jouyban-Acree and Jouyban-Acree-van't Hoff models. The resp. apparent thermodn. functions (Gibbs energy, enthalpy, and entropy of the dissoln. processes) were computed using the van't Hoff and Gibbs equations. The enthalpy-entropy relationship for ketoconazole was non-linear in the plot of enthalpy vs. Gibbs energy of soln. with neg. slope in the compn. region 0.00 ≤ w1 ≤ 0.20 but pos. slope in the region 0.20 ≤ w1 ≤ 0.70. Beyond this compn., the behavior is more complex. In addn., the inverse Kirkwood-Buff integrals were used to investigate the preferential solvation of ketoconazole which is preferentially solvated by water mols. in water-rich and also in ethanol-rich mixts. but preferentially solvated by ethanol mols. in mixts. 0.24 ≤ x1 ≤ 0.75. Dissoln. thermodn. and preferential solvation computations were carried out employing whole exptl. soly. data points and the simulated data using a min. no. of seven data points as training set, in which there were no significant differences in the obtained numerical values except for enthalpy-entropy compensation data.
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    22. 22
      Jahromi, R.; Mogharab, V.; Jahromi, H.; Avazpour, A. Synergistic effects of anionic surfactants on coronavirus (SARS-CoV-2) virucidal efficiency of sanitizing fluids to fight COVID-19. Food Chem. Toxicol. 2020, 145, 111702,  DOI: 10.1016/j.fct.2020.111702
      22
      Synergistic effects of anionic surfactants on coronavirus (SARS-CoV-2) virucidal efficiency of sanitizing fluids to fight COVID-19
      Jahromi, Reza; Mogharab, Vahid; Jahromi, Hossein; Avazpour, Arezoo
      Food and Chemical Toxicology (2020), 145 (), 111702CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
      Our surrounding environment, esp. often-touched contaminated surfaces, plays an important role in the transmission of pathogens in society. The shortage of effective sanitizing fluids, however, became a global challenge quickly after the coronavirus disease-19 (COVID-19) outbreak in Dec. 2019. In this study, we present the effect of surfactants on coronavirus (SARS-CoV-2) virucidal efficiency in sanitizing fluids. Sodium dodecylbenzenesulfonate (SDBS), sodium laureth sulfate (SLS), and two com. dish soap and liq. hand soap were studied with the goal of evapn. rate redn. in sanitizing liqs. to maximize surface contact time. Twelve fluids with different recipes composed of ethanol, isopropanol, SDBS, SLS, glycerin, and water of standardized hardness (WSH) were tested for their evapn. time and virucidal efficiency. Evapn. time increased by 17-63% when surfactant agents were added to the liq. In addn., surfactant incorporation enhanced the virucidal efficiency between 15 and 27% according to the 4-field test in the EN 16615:2015 European Std. method. Most importantly, however, we found that surfactant addn. provides a synergistic effect with alcs. to inactivate the SARS-CoV-2 virus. This study provides a simple, yet effective soln. to improve the virucidal efficiency of commonly used sanitizers.
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    23. 23
      Osborne, D. W.; Musakhanian, J. Skin Penetration and Permeation Properties of Transcutol®-Neat or Diluted Mixtures. AAPS PharmSciTech 2018, 19, 3512– 3533,  DOI: 10.1208/s12249-018-1196-8
      23
      Skin Penetration and Permeation Properties of Transcutol-Neat or Diluted Mixtures
      Osborne, David W.; Musakhanian, Jasmine
      AAPS PharmSciTech (2018), 19 (8), 3512-3533CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
      A review. A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by phys. means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) com. known as Transcutol. Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol. In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to exptl. variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol influences skin penetration and permeation. [Figure not available: see fulltext.].
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    24. 24
      Roy, C.; Charkrabarty, J. Stability indicating validated novel RP-HPLC method for simulataneous estimation of methylparaben, ketoconazole and mometasone furoate in topical pharmaceutical dosage formulation. ISRN Anal. Chem. 2013, 1,  DOI: 10.1155/2013/342794
      There is no corresponding record for this reference.
    25. 25
      Harris, R.; Jones, H. E.; Artis, W. M. Orally Administered Ketoconazole: Route of Delivery to the Human Stratum Corneum. Antimicrob. Agents Chemother. 1983, 876– 882,  DOI: 10.1128/AAC.24.6.876
      25
      Orally administered ketoconazole: route of delivery to the human stratum corneum
      Harris, Russell; Jones, Henry E.; Artis, William M.
      Antimicrobial Agents and Chemotherapy (1983), 24 (6), 876-82CODEN: AMACCQ; ISSN:0066-4804.
      Healthy volunteers, patients with chronic fungal disease, and a patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole (I) [65277-42-1] daily for various lengths of time. Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 μg ketoconazole/g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from patients with chronic fungal infection treated for >9 mo contained ketoconazole (4.7 μg/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 μg/mL on day 7 and 0.084 μg/mL on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole contg. eccrine sweat demonstrated a 10-fold greater concn. in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. Thus, eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids.
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    26. 26
      Hildebrand, J. H.; Scott, R. L. Regular solutions; Prentice-Hall: Saddle River, NJ, USA, 1962; pp. 202.
      There is no corresponding record for this reference.
    27. 27
      Hildebrand, J. H.; Scott, R. L. The solubility of nonelectrolytes; Reinhold Pub. Corp.: New York, NY, USA, 1950; pp. 514.
      There is no corresponding record for this reference.
    28. 28
      Hansen, C. M. Hansen solubility parameters: A User’s Handbook; 2nd ed.; CRC Press: Boca Raton, FL, USA, 2007; pp. 544.
      There is no corresponding record for this reference.
    29. 29
      Ruidiaz, M. A.; Delgado, D. R.; Martínez, F.; Marcus, Y. Solubility and preferential solvation of indomethacin in 1,4-dioxane + water solvent mixtures. Fluid Phase Equilib. 2010, 299, 259– 265,  DOI: 10.1016/j.fluid.2010.09.027
      29
      Solubility and preferential solvation of indomethacin in 1,4-dioxane + water solvent mixtures
      Ruidiaz, Miller A.; Delgado, Daniel R.; Martinez, Fleming; Marcus, Yizhak
      Fluid Phase Equilibria (2010), 299 (2), 259-265CODEN: FPEQDT; ISSN:0378-3812. (Elsevier B.V.)
      The solubilities of indomethacin (IMC) in 1,4-dioxane + water cosolvent mixts. were detd. at several temps., 293.15-313.15 K. The thermodn. functions: Gibbs energy, enthalpy, and entropy of soln. and of mixing were obtained from these data by using the van't Hoff and Gibbs equations. The soly. was maximal in 0.95 mass fraction of 1,4-dioxane and very low in pure water at all the temps. A non-linear plot of ΔHsoln° vs. ΔGsoln° with neg. slope from pure water up to 0.60 mass fraction of 1,4-dioxane and pos. beyond this up to 0.95 mass fraction of 1,4-dioxane was obtained. Accordingly, the driving mechanism for IMC soly. in water-rich mixts. is the entropy, probably due to water-structure loss around the drug non-polar moieties by 1,4-dioxane, whereas, above 0.60 mass fraction of 1,4-dioxane the driving mechanism is the enthalpy, probably due to IMC solvation increase by the co-solvent mols. The preferential solvation of IMC by the components of the solvent was estd. by means of the quasi-lattice quasi-chem. method, whereas the inverse Kirkwood-Buff integral method could not be applied because of divergence of the integrals in intermediate compns.
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    30. 30
      Williams, R. O. B. Solubility and Solubilization in Aqueous Media By Samuel H. Yalkowsky (University of Arizona). Oxford University Press: New York. 1999. xvi + 464 pp. $165. ISBN 0-8412-3576-7. J. Am. Chem. Soc. 2000, 122, 9882,  DOI: 10.1021/ja0047424
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      Solubility and Solubilization in Aqueous Media. By Samuel H. Yalkowsky (University of Arizona). Oxford University Press: New York. 1999. xvi + 464 pp. $165. ISBN 0-8412-3576-7.
      Williams, Robert O., III
      Journal of the American Chemical Society (2000), 122 (40), 9882CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      There is no expanded citation for this reference.
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    31. 31
      Apelblat, A.; Manzurola, E. Solubilities ofo-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic andp-toluic acid and magnesium-DL-aspartate in water from T = 20 (278–348) K. J. Chem. Thermodyn. 1999, 31, 85– 91,  DOI: 10.1006/jcht.1998.0424
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      Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water from T=(278 to 348) K
      Apelblat, Alexander; Manzurola, Emanuel
      Journal of Chemical Thermodynamics (1999), 31 (1), 85-91CODEN: JCTDAF; ISSN:0021-9614. (Academic Press)
      Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water were detd. in the temp. range (278 to 345) K. The apparent molar enthalpies of soln. at T=298.15 K were derived from these solubilities, and the resulting values are ΔsolHm(o-C9H8O4, m=0.0226 mol·kg-1)=22.9 kJ·mol-1, ΔsolHm(4-C7H7O3N, m=0.00758 mol·kg-1)=26.1 kJ·mol-1, ΔsolHm(3,5-C7H4O7N2, m=0.0633 mol·kg-1)=28.7 kJ·mol-1, ΔsolHm(p-C8H8O2, m=0.00258 mol·kg-1)=24.0 kJ·mol-1, and ΔsolHm(dl-C8H12O3N2Mg, m=0.1485 mol·kg-1)=11.7 kJ·mol-1. (c) 1999 Academic Press.
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    32. 32
      Manzurola, E.; Apelblat, A. Solubilities of L-glutamic acid, 3-nitrobenzoic acid, acetylsalicylic, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL- aspartate, and magnesium-L-lactate in water. J. Chem. Thermodyn. 2002, 34, 1127– 1136,  DOI: 10.1006/jcht.2002.0975
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      Solubilities of L-glutamic acid, 3-nitrobenzoic acid, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL-aspartate, and magnesium-L-lactate in water
      Manzurola, Emanuel; Apelblat, Alexander
      Journal of Chemical Thermodynamics (2002), 34 (7), 1127-1136CODEN: JCTDAF; ISSN:0021-9614. (Elsevier Science Ltd.)
      Solubilities of L-glutamic acid, 3-nitrobenzoic acid, p-toluic acid, calcium-L-lactate, calcium gluconate, magnesium-DL-aspartate, and magnesium-L-lactate in water were detd. in the temp. range 278 to 343 K. The apparent molar enthalpies of soln. at T = 298.15 K as derived from these solubilities are ΔsolHm(L-glutamic acid, msat = 0.0565 mol·kg-1) = 30.2 kJ·mol-1, ΔsolHm(3-nitrobenzoic acid, m =0.0188 mol·kg-1) = 28.1 kJ·mol-1, ΔsolHm(p-toluic acid, m = 0.00267 mol·kg-1) = 23.9 kJ·mol-1, ΔsolHm(calcium-L-lactate tetrahydrate, m = 0.2902 mol·kg-1) = 25.8 kJ·mol-1, ΔsolHm(calcium gluconate, m = 0.0806 mol·kg-1) = 22.1 kJ·mol-1, ΔsolHm(magnesium-DL-aspartate tetrahydrate, m = 0.1469 mol·kg-1) = 11.5 kJ·mol-1, and ΔsolHm(magnesium-L-lactate trihydrate, m = 0.3462 mol·kg-1) = 3.81 kJ·mol-1.
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    33. 33
      Krug, R. R.; Hunter, W. G.; Grieger, R. A. Enthalpy-entropy compensation. 2. Separation of the chemical from the statistic effect. J. Phys. Chem. 1976, 80, 2341– 2351,  DOI: 10.1021/j100562a007
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      Enthalpy-entropy compensation. 2. Separation of the chemical from the statistical effect
      Krug, R. R.; Hunter, W. G.; Grieger, R. A.
      Journal of Physical Chemistry (1976), 80 (21), 2341-51CODEN: JPCHAX; ISSN:0022-3654.
      For problems concerning enthalpy-entropy compensations, an appropriate regression procedure is presented for the estn. of functional dependencies between thermodn. parameters. Unbiased parameter ests. and their confidence intervals are derived for the case of a linear dependence between thermodn. parameters. It is demonstrated that nonlinear as well as linear functional dependencies are readily detectable when enthalpy ests. are plotted vs. free energy ests. Some linear and nonlinear examples of functional dependencies between thermodn. parameters are analyzed and discussed.
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