# Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination, Hansen Solubility Parameters, Correlation, and Thermodynamics

^{1}

^{2}

^{*}

## Abstract

**:**

^{−2}at 313.2 K) followed by the minimum in neat water (3.91 × 10

^{−8}at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the “Apelblat, van’t Hoff, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree–van’t Hoff models”, respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.

## 1. Introduction

_{26}H

_{28}N

_{2}, and molar mass: 368.50 g mol

^{−1}) appears as a white crystalline powder [1,2]. It is used as an antihistaminic and blood-flow promoter [2,3]. The biopharmaceutical classification system (BCS) classifies it as a BCS class II drug, meaning it has poor aqueous solubility and high permeability [1,4]. It is a weak base, which is practically insoluble in water with a high partition coefficient value (log P = 5.8) [5]. Hence, the bioavailability and oral absorption of CNZ are limited by its low solubility and poor dissolution rate [1]. CNZ is a non-efficient drug molecule due to its low solubility, stability, and poor bioavailability from a physicochemical viewpoint [1,2,3,4,5]. Various lipid-based drug delivery systems, such as self-nanoemulsifying drug delivery systems (SNEDDS) and solidified SNEDDS, have been developed to modify the physicochemical characteristics of CNZ [2,6,7,8,9,10,11,12,13,14].

^{−1}in an aqueous buffer with pH = 2.0, 0.017 mg mL

^{−1}, pH = 5.0, and 0.002 mg mL

^{−1}, pH = 6.5 at 310.2 K [2]. The solubility of CNZ has also been reported in water and four organic solvents such as acetonitrile, butyl acetate, 1-butanol, and 2-propanol between 288.15 and 313.15 K [1].

## 2. Results and Discussion

#### 2.1. Mole Fraction Solubility Data of CNZ

^{−8}, 7.71 × 10

^{−8}, and 9.35 × 10

^{−8}at 298.3 K, 303.0 K, and 307.8 K, respectively [1]. The mole fraction solubility of CNZ in water was determined to be 5.67 × 10

^{−8}, 7.82 × 10

^{−8}, and 9.78 × 10

^{−8}at three closed temperatures of 298.2 K, 303.2 K, and 308.2 K, respectively. In neat water, these CNZ mole fraction solubility values were similar to those previously reported in the literature [1].

#### 2.2. Hansen Solubility Parameters (HSPs)

_{t}) for CNZ was estimated to be 19.40 MPa

^{1/2}using HSPiP software and Equation (1). HSP values for neat TP (δ

_{1}) and neat water (δ

_{2}) were anticipated to be 21.40 and 47.80 MPa

^{1/2}, respectively. Equation (2) was used to calculate the HSP value for various {TP (1) + water (2)} combinations free of CNZ (δ

_{mix}). The δ

_{mix}values were estimated to be between 24.04 and 45.16 MPa

^{1/2}. Overall, the HSP of neat TP (δ

_{1}= 21.40 MPa

^{1/2}) and CNZ (δ

_{t}= 19.40 MPa

^{1/2}) were very close. The solubility of CNZ in neat TP was likewise found to be the highest in the experiments. As a result, these findings were in good accord with the CNZ solubility data obtained from experiments with {TP (1) + water (2)} combinations.

#### 2.3. Cosolvency-Based Mathematical Models for CNZ Solubility Correlation

^{2}) for CNZ (3) in all cosolvent combinations with neat solvents was obtained at between 0.9955 and 0.9998. These findings revealed a strong connection between the experimental CNZ (3) solubility data and the modified “Apelblat model” in binary {TP (1) + water (2)} combinations.

^{2}for CNZ (3) in all cosolvent mixtures with neat solvents was obtained at between 0.9947 and 0.9993. These findings also revealed a strong connection between experimental CNZ (3) solubility data and the “van’t Hoff model” in binary {TP (1) + water (2)} combinations.

#### 2.4. Apparent Thermodynamic Parameters for CNZ

_{soln}H°) values for CNZ (3) in all cosolvent mixtures, including neat solvents, were calculated using the van’t Hoff technique. As reported in Table 5, Figure 3 displays the linear van’t Hoff curves of CNZ (3) in all cosolvent compositions and pure solvents where R

^{2}was more than 0.990. Table 5 also includes the values of all thermodynamic quantities. The CNZ (3) Δ

_{soln}H° values in binary {TP (1) + water (2)} combinations with pure solvents ranged from 9.719 to 47.65 kJ mol

^{−1}. In various {TP (1) + water (2)} mixtures including neat solvents, the apparent standard Gibbs energy (Δ

_{soln}G°) values for CNZ (3) were computed between 7.492 and 41.32 kJ mol

^{−1}. The endothermic dissolution of CNZ (3) in various {TP (1) + water (2)} combinations with pure solvents was demonstrated by the obtained values of Δ

_{soln}H° for CNZ [18,19]. The Δ

_{soln}H° and Δ

_{soln}G° values are inversely proportional to the solubility of the solute. Hence, the maximum Δ

_{soln}H° and Δ

_{soln}G° values for CNZ were obtained in neat water compared to the neat TP. The apparent standard entropy (Δ

_{soln}S°) values for CNZ (3) in binary {TP (1) + water (2)} combinations with neat solvents were computed between 7.346 and 23.94 J mol

^{−1}K

^{−1}, implying the entropy-driven dissolution of CNZ (3) in diverse {TP (1) + water (2)} combinations with pure solvents [18]. Finally, in all {TP (1) + water (2)} combinations, including pure solvents, the dissolution of CNZ (3) was reported to be endothermic and entropy-driven [18,19].

#### 2.5. Enthalpy–Entropy Compensation Analysis

_{soln}H° vs. Δ

_{soln}G° trend in all {TP (1) + water (2)} combinations with pure solvents, with a slope value of 1.124 and R

^{2}= 0.997. Based on these findings, the driving mechanism for CNZ (3) solvation in all {TP (1) + water (2)} combinations, including neat solvents, is assumed to be enthalpy-driven. This method of CNZ solvation could be explained by the fact that CNZ solvates best in neat TP molecules compared to neat water molecules [19,28]. As a result, the molecular interactions between CNZ–TP molecules were stronger than those between CNZ–water molecules. This solvation behavior of CNZ (3) in binary {TP (1) + water (2)} combinations with pure solvents was identical to that of flufenamic acid, piperine, sinapic acid, sunitinib malate, apigenin, and apremilast in binary {TP (1) + water (2)} combinations [18,19,20,29,30,31].

## 3. Materials and Methods

#### 3.1. Materials

#### 3.2. CNZ (3) Solubility Determination in Binary {TP (1) + Water (2)} Combinations

_{1}= 0.0–1.0; w

_{1}is TP mass fraction in {TP (1) + water (2)} compositions) and pure solvents was tested from 293.2–313.2 K and at 0.1 MPa in various {TP (1) + water (2)} mixtures and pure solvents. Extra CNZ crystals were mixed with known amounts of each {TP (1) + water (2)} composition and neat solvents. Three repetitions of each experiment were carried out. Inside the Biological Shaker (Julabo, PA, USA), the acquired samples were saturated for three days to achieve equilibrium. After reaching equilibrium, the saturated samples were withdrawn from the shaker and centrifuged at 5000 rpm. The supernatants were withdrawn, diluted (wherever applicable), and used for the estimation of CNZ content using a reported HPLC method at 253 nm [12]. The mole fraction solubilities (x

_{e}) of CNZ were calculated using their standard formulae [20,33].

#### 3.3. HSPs of CNZ and Various {TP (1) + Water (2)} Mixtures

_{t}value for CNZ, neat TP, and neat water was predicted using Equation (1) [35,36,37,38]:

_{d}= dispersion HSP; δ

_{p}= polar HSP, and δ

_{h}= hydrogen-bonded HSP. These values for CNZ and neat solvents were predicted utilizing HSPiP software (version 4.1.07, Louisville, KY, USA) by entering the simplified molecular input line entry system (SMILES) of each component into the HSPiP system [36].

_{mix}) was calculated using Equation (2) [38]:

_{1}= HSP of neat TP, and δ

_{2}= HSP of neat water.

#### 3.4. Cosolvency-Based Mathematical Models for CNZ Solubility Correlation

^{Apl})” of CNZ (3) in binary {TP (1) + water (2)} combinations was predicted using Equation (3) [24,25]:

_{e}and x

^{Apl}of CNZ was performed using MPD. The MPD was calculated using its reported formula [27].

^{van’t})” of CNZ (3) in binary {TP (1) + water (2)} combinations is predicted using Equation (4) [20]:

^{Yal})” for CNZ (3) in various {TP (1) + water (2)} combinations was predicted by Equation (5) [26]:

_{1}= the solubility of CNZ (3) in TP (1); x

_{2}= the solubility of CNZ in water (2); w

_{1}= TP mass fraction, and w

_{2}= water mass fraction. Equation (5) models the solubility values of pharmaceutical compounds in different solvent mixtures at a given temperature.

_{m,T}), and was predicted using Equation (6) [27]:

_{1,T}and x

_{2,T}are the solubility of CNZ in TP (1) and water (2) at temperature T, and the symbols J are the model parameters. The solubility values of CNZ in pure solvents are required as input data to predict the solubility of CNZ in cosolvent compositions at the temperature of interest. To overcome this constraint, Equations (2) and (6) can be combined to form the “Jouyban–Acree–van’t Hoff model” [27].

#### 3.5. Apparent Thermodynamic Parameters for CNZ

_{hm}), all apparent thermodynamic parameters were examined. The T

_{hm}was calculated using the usual formula [27]. In this study, the T

_{hm}was found to be 303.0 K. An apparent thermodynamic analysis was used to calculate several apparent thermodynamic parameters. The van’t Hoff and Gibbs equations were used to conduct this analysis. Equation (7) was used to determine the Δ

_{soln}H° values for CNZ (3) in binary {TP (1) + water (2)} combinations at T

_{hm}= 303.0 K using the van’t Hoff methodology [28,41]:

_{e}values of CNZ vs. (1/T−1/T

_{hm}), the Δ

_{soln}H° and Δ

_{soln}G° values for CNZ were calculated from the slope and intercept, using the following Equations (8) and (9), respectively [28,41]:

#### 3.6. Enthalpy–Entropy Compensation Analysis

## 4. Conclusions

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

## Sample Availability

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**Figure 2.**Influence of Transcutol-P (TP) mass fraction (w

_{1}) on logarithmic solubilities of CNZ between 293.2 and 313.2 K.

**Figure 3.**Van’t Hoff curves for logarithmic solubility of CNZ (3) in aqueous mixtures of TP (1) and water (2).

**Figure 4.**Δ

_{sol}H° vs. Δ

_{sol}G° enthalpy–entropy compensation plot for solubility of CNZ in various {TP (1) + water (2)} mixtures at T

_{hm}= 303.0 K.

**Table 1.**Solubility values (x

_{e}) of cinnarizine (CNZ) in mole fraction (3) in binary {Transcutol-P (TP) (1) + water (2)} combinations from 293.2–313.2 K and at 0.1 MPa

^{a}.

w_{1}^{a} | x_{e}^{b} | ||||
---|---|---|---|---|---|

T = 293.2 K | T = 298.2 K | T = 303.2 K | T = 308.2 K | T = 313.2 K | |

0.0 | 3.91 × 10^{−8} | 5.67 × 10^{−8} | 7.82 × 10^{−8} | 9.78 × 10^{−8} | 1.42 × 10^{−7} |

0.1 | 1.66 × 10^{−7} | 2.30 × 10^{−7} | 3.16 × 10^{−7} | 3.91 × 10^{−7} | 5.30 × 10^{−7} |

0.2 | 6.50 × 10^{−7} | 8.87 × 10^{−7} | 1.23 × 10^{−6} | 1.51 × 10^{−6} | 1.95 × 10^{−6} |

0.3 | 2.64 × 10^{−6} | 3.50 × 10^{−6} | 4.49 × 10^{−6} | 5.35 × 10^{−6} | 7.00 × 10^{−6} |

0.4 | 1.12 × 10^{−5} | 1.42 × 10^{−5} | 1.72 × 10^{−5} | 2.09 × 10^{−5} | 2.62 × 10^{−5} |

0.5 | 4.24 × 10^{−5} | 5.26 × 10^{−5} | 6.34 × 10^{−5} | 7.33 × 10^{−5} | 9.22 × 10^{−5} |

0.6 | 1.73 × 10^{−4} | 2.10 × 10^{−4} | 2.44 × 10^{−4} | 2.77 × 10^{−4} | 3.36 × 10^{−4} |

0.7 | 6.89 × 10^{−4} | 8.00 × 10^{−4} | 9.22 × 10^{−4} | 1.05 × 10^{−3} | 1.23 × 10^{−3} |

0.8 | 2.81 × 10^{−3} | 3.17 × 10^{−3} | 3.53 × 10^{−3} | 3.90 × 10^{−3} | 4.43 × 10^{−3} |

0.9 | 1.12 × 10^{−2} | 1.25 × 10^{−2} | 1.38 × 10^{−2} | 1.48 × 10^{−2} | 1.62 × 10^{−2} |

1.0 | 4.52 × 10^{−2} | 4.78 × 10^{−2} | 5.08 × 10^{−2} | 5.44 × 10^{−2} | 5.83 × 10^{−2} |

^{a}The uncertainties u are u(T) = 0.2 K, u(w

_{1}) = 0.0007, and u(p) = 2 kPa.

^{b}The relative uncertainty u

_{r}in solubility is u

_{r}(x

_{e}) = 0.016.

**Table 2.**Results for the modified “Apelblat model” for CNZ (3) in various {TP (1) + water (2)} combinations.

w_{1} | A | B | C | R^{2} | MPD (%) |
---|---|---|---|---|---|

0.0 | 224.09 | −15741 | −32.997 | 0.9956 | - |

0.1 | 286.07 | −18057 | −42.264 | 0.9979 | - |

0.2 | 442.94 | −24887 | −65.536 | 0.9980 | - |

0.3 | 211.39 | −13815 | −31.176 | 0.9969 | - |

0.4 | −25.275 | −2611.0 | 4.0112 | 0.9988 | - |

0.5 | 8.3136 | −3761.7 | −0.97648 | 0.9957 | 2.27 |

0.6 | 53.365 | −5294.9 | −7.7389 | 0.9956 | - |

0.7 | −72.315 | 715.43 | 11.018 | 0.9955 | - |

0.8 | −46.705 | 101.83 | 7.1263 | 0.9981 | - |

0.9 | 127.04 | −7373.2 | −18.728 | 0.9994 | - |

1.0 | −132.56 | 4855.2 | 19.875 | 0.9998 | - |

**Table 3.**Resulting data for “van’t Hoff model” for CNZ (3) in different {TP (1) + water (2)} combinations.

w_{1} | a | b | R^{2} | MPD (%) |
---|---|---|---|---|

0.0 | 2.5154 | −5733.0 | 0.9947 | |

0.1 | 2.2793 | −5240.5 | 0.9967 | |

0.2 | 2.8838 | −5015.9 | 0.9953 | |

0.3 | 2.0440 | −4360.6 | 0.9959 | |

0.4 | 1.6487 | −3824.2 | 0.9987 | |

0.5 | 1.7473 | −3462.8 | 0.9954 | 5.15 |

0.6 | 1.3939 | −2946.3 | 0.9952 | |

0.7 | 1.6646 | −2623.1 | 0.9993 | |

0.8 | 1.1397 | −2057.0 | 0.9978 | |

0.9 | 1.2918 | −1694.4 | 0.9973 | |

1.0 | 0.88450 | −1169.3 | 0.9960 |

**Table 4.**Resulting data for “Yalkowsky–Roseman model” for CNZ (3) in different {TP (1) + water (2)} combinations from 293.2–313.2 K.

w_{1} | log x^{Yal} | MPD (%) | ||||
---|---|---|---|---|---|---|

T = 293.2 K | T = 298.2 K | T = 303.2 K | T = 308.2 K | T = 313.2 K | - | |

0.1 | −6.80 | −6.65 | −6.52 | −6.43 | −6.28 | - |

0.2 | −6.19 | −6.06 | −5.94 | −5.86 | −5.72 | - |

0.3 | −5.58 | −5.46 | −5.36 | −5.28 | −5.16 | - |

0.4 | −4.98 | −4.87 | −4.78 | −4.71 | −4.60 | 24.76 |

0.5 | −4.37 | −4.28 | −4.20 | −4.13 | −4.04 | - |

0.6 | −3.77 | −3.69 | −3.61 | −3.56 | −3.47 | - |

0.7 | −3.16 | −3.09 | −3.03 | −2.98 | −2.91 | - |

0.8 | −2.55 | −2.50 | −2.45 | −2.41 | −2.35 | - |

0.9 | −1.95 | −1.91 | −1.87 | −1.83 | −1.79 | - |

**Table 5.**Apparent standard enthalpy (Δ

_{soln}H°), apparent standard Gibbs energy (Δ

_{soln}G°), apparent standard entropy (Δ

_{soln}S°), and van’t Hoff R

^{2}values for CNZ (3) in different {TP (1) + water (2)} combinations at T

_{hm}= 303.0 K

^{a}.

w_{1} | Δ_{soln}H°/kJ mol^{−1} | Δ_{soln}G°/kJ mol^{−1} | Δ_{soln}S°/J mol^{−1} K^{−1} | R^{2} |
---|---|---|---|---|

0.0 | 47.65 | 41.32 | 20.48 | 0.994 |

0.1 | 43.56 | 37.82 | 18.92 | 0.996 |

0.2 | 41.69 | 34.43 | 23.94 | 0.995 |

0.3 | 36.24 | 31.10 | 16.96 | 0.995 |

0.4 | 31.78 | 27.64 | 13.68 | 0.998 |

0.5 | 28.78 | 24.38 | 14.50 | 0.995 |

0.6 | 24.49 | 20.98 | 11.57 | 0.995 |

0.7 | 21.80 | 17.61 | 13.82 | 0.999 |

0.8 | 17.09 | 14.23 | 9.464 | 0.997 |

0.9 | 14.08 | 10.83 | 10.72 | 0.997 |

1.0 | 9.719 | 7.492 | 7.346 | 0.996 |

^{a}The relative uncertainties are u

_{r}(Δ

_{soln}H

^{0}) = 0.043, u

_{r}(Δ

_{soln}G

^{0}) = 0.045, and u

_{r}(Δ

_{soln}S

^{0}) = 0.034.

Material | Molecular Formula | Molar Mass (g mol^{−1}) | CAS RN | Purification Method | Mass Fraction Purity | Analysis Method | Source |
---|---|---|---|---|---|---|---|

CNZ | C_{26}H_{28}N_{2} | 368.50 | 298-57-7 | None | >0.99 | HPLC | FDC Ltd. |

TP | C_{6}H_{14}O_{3} | 134.17 | 111-90-0 | None | >0.99 | GC | Gattefosse |

Water | H_{2}O | 18.07 | 7732-18-5 | None | - | - | Milli-Q |

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## Share and Cite

**MDPI and ACS Style**

Shakeel, F.; Kazi, M.; Alanazi, F.K.; Alam, P.
Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination, Hansen Solubility Parameters, Correlation, and Thermodynamics. *Molecules* **2021**, *26*, 7052.
https://doi.org/10.3390/molecules26227052

**AMA Style**

Shakeel F, Kazi M, Alanazi FK, Alam P.
Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination, Hansen Solubility Parameters, Correlation, and Thermodynamics. *Molecules*. 2021; 26(22):7052.
https://doi.org/10.3390/molecules26227052

**Chicago/Turabian Style**

Shakeel, Faiyaz, Mohsin Kazi, Fars K. Alanazi, and Prawez Alam.
2021. "Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination, Hansen Solubility Parameters, Correlation, and Thermodynamics" *Molecules* 26, no. 22: 7052.
https://doi.org/10.3390/molecules26227052