Thermal Analysis Investigation of Dapoxetine and Vardenafil Hydrochlorides using Molecular Orbital Calculations

© 2015 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers. Adv Pharm Bull, 2015, 5(4), 523-529 doi: 10.15171/apb.2015.071 http://apb.tbzmed.ac.ir Advanced Pharmaceutical Bulletin


Introduction
Dapoxetine hydrochloride (DAP) is designated chemically as N, N dimethyl-3-(naphthalen-1-yloxy)-1phenylpropan-1-amine.It is mainly used as selective short acting potent serotonin reuptake inhibitor (SSRI).It is effective for the treatment of premature ejaculation in men. 1,2ardenafil hydrochloride (VAR), is chemically 2-[2ethoxy-5(4-ethyl-piperazine-1-sul-phonyl)-phenyl]-5methyl-7-propyl-3H-imidazo 5,1-f] [1-3] triazin-4-one hydrochloride.It is used to treat erectile dysfunction. 3hermal analysis has been an extremely important analytical tool within the pharmaceutical industry where the rapid advances in pharmaceutical industries have led to an increased demand for the chemical and structural information about the pharmaceutical systems.Thermal analysis is a group of techniques in which the variation of a physical property of a substance is measured as a function of temperature.The most commonly used are those which measure changes of mass or changes in energy of a sample of a substance.These techniques such as thermogravimetric analysis (TGA), derivative thermogravimetry (DrTGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC) provide unique information in relation to thermodynamic data of the system studies.[6][7][8][9][10][11][12][13][14][15][16] No previous publications were made before for the study of thermal behavior of DAP and VAR.Therefore, the present work aimed to study the thermal behavior of DAP and VAR using different techniques such as TGA, DrTGA, DTA and DSC, the results were confirmed using semi-empirical molecular orbital calculations to determine the weakest bonds ruptured during thermal degradation of the used drugs.[19][20][21]

Instruments and Methods
Thermal analysis studies were made by using simultaneous TGA-DTA thermal analyzer apparatus (Shimadzu DTG-60H).The experiments were performed between ambient and 800 o C. The temperature program had a heating rate 10 °C min -1 .Dry nitrogen at a flow rate of 30 mL min -1 was used as the purge gas.α-Al 2 O 3 was used as the reference material.][19][20][21] Thermodynamic parameters such as Arrhenius constant (A), activation energy (E), enthalpy (H), entropy (S) and Gibbs free energy (G) were calculated using Horowitz-Metzger and Coats-Redfern methods. 22,23C curves were measured on Shimadzu DSC-50 cell.Approximately 3 mg of samples were mass out and placed in a sealed aluminum pan.An empty aluminum pan was used as a reference.The purity determination was performed in temperature range from 25 to 500 °C in nitrogen atmosphere with flow rate of 30 mL min -1 using heating rate of 10 °C min -1 .DSC equipment was preliminary calibrated with standard of indium.

Results and Discussion
Thermal analysis of DAP and VAR Figure 1 shows the TGA, DrTGA and DTA curves of DAP and VAR.DAP is thermally stable up to 158.12 °C, and then decomposes in two steps.The thermal decomposition of VAR occurs in five consecutive steps.For DAP, the first step occurs in two consecutive stages, the first stage at temperature range 158.12-246.39°C is due to the loss of HCl molecule (Mass loss: Found 10.451%, Calc.10.676%) and the second stage is due to the loss of C 17 H 19 NO (Mass loss: Found 73.483%, Calc.74.0%) at 246.39-330.32 °C.The second step occurs at 330.32-602.10o C with the loss of C 4 H 4 (Mass loss: Found 15.497%, Calc.15.21%).These results indicate the compatibility between mass fragmentation and thermal degradation of DAP. 24he DTA curve of DAP shows two endothermic peaks and two exothermic peaks.The first endothermic peak at 183.57°C is sharp and may be attributed to the melting point of DAP, this value is close to the reported melting point of DAP (179-183 °C). 25 The second endothermic peak at 288.06 °C and the exothermic peak at 309.88 °C are broad and may be due to the loss of HCl and C 17 H 19 NO.Very strong and sharp exothermic peak at 553.70 °C may be due to the loss of C 4 H 4 .For VAR, the first step occurs in the temperature range from 22.84 °C to 191.84 °C with the loss of HCl molecule 6.285% (Mass loss: Found 6.285%, Calc.6.303%).The second step occurs at 191.84-245.38 °C with the loss of three molecules of water (Mass loss: Found 9.342%, Calc.9.324%).The third step occurs at 245.38-370.60 °C due to the mass losses of SO 2 , C 6 H 13 N 2 , C 3 H 7 and CH 3 (Mass loss: Found 40.872%,Calc.40.580%).The fourth step occurs at 370.60-476.10°C due to loss of C 3 N 2 (Mass loss: Found 11.077%, Calc.11.051%).It is followed by the fifth practical weight loss of 32.904%.This loss may be due to the complete decomposition of C 10 H 7 N 2 O 2 that occurs at 476.10-640.02°C (Mass loss: Calc.32.291%).These results indicate that, the compatibility between mass fragmentation and thermal degradation of VAR. 26 The DTA curve of VAR shows four endothermic peaks and an exothermic peak.The first weak endothermic peak at 108.50 °C may be attributed to the loss of HCl molecule.The second endothermic peak at 218.38 °C may be attributed to melting point of VAR, this value is very close to the reported melting point of VAR (218 °C) 25 the melting process is accompanied with the loss of three molecules of water.The third endothermic peak at 295.20 °C may be due to the losses of SO 2 , C 6 H 13 N 2 , C 3 H 7 and CH 3 .The fourth endothermic peak at 406.48 °C may be due to the loss of C 3 N 2 .Very strong and sharp exothermic peak at 577.8 °C may be due to the loss of C 10 H 7 N 2 O 2 .Figure 2 shows the thermal decomposition pattern of DAP and VAR.

MO calculations of DAP and VAR
MO calculations depending on numbering system of DAP and VAR give variable information about the structure of the molecules which actually be used to support the experimental results.

Thermodynamic parameters of DAP and VAR
Horowitz-Metzger (HM) and Coats-Redfern (CR) methods were applied for calculating the activation energy (E) values required for the mass losses during thermal decomposition steps of DAP and VAR and the other thermodynamic parameters (A, S, H and G).The negative values of S may refer to the stability of the loosed fragments obtained as a result of thermal decomposition of DAP and VAR, on the other hand the of the second step of decomposition of DAP shows high positive values of S (168.45 (HM) and 123.17 (CR) J mol -1 K -1 ) may refer to the high activity and volatility of the loosed C 4 H 4 fragments.The results are listed in Table 1, from these results we conclude that DAP is more stable than VAR.

Determination of purity of DAP and VAR
The determination of purity of the used compounds in chemistry is very important, chromatographic methods are used to determine purity of the used compounds in comparison with a standard samples.On the other hand, DSC technique can be used for the determination of purity based on the assumption that the impurities will lower the melting point of a pure substance.The melting transition of pure (100% crystalline substance) should be infinitely sharp, but impurities or defects in the crystal structure will broaden the melting range and lower the melting point. 27In a system which contains impurities, Van ' t Hoff equation approximately holds and allows the purity value to be calculated as follow: T f = T 0 -[(R T 0 2 x/∆H f ).1/F] where T f is the melting temperature of the sample, T 0 is the melting point of pure substance in Kelvin (K), R is the gas constant, ∆H f is the heat of fusion, F is fraction of sample melted at T f , and x is mole fraction of impurities in the original sample.Table 1.Thermodynamic parameters of thermal decomposition of DAP and VAR.

Temperature range (°C) E (KJ mol -1 ) HM (CR) A (S -1 ) HM (CR)
S (J mol   The purity values of DAP and VAR are found to be 99.97% and 99.95%, respectively.These values are very good when compared with the purity of the used drugs 99.92% and 99.94% for DAP and VAR, respectively.DSC curve of VAR shows two weak endothermic peaks at 255.86 °C and 290.81 °C and medium endothermic peak at 278.51 °C.The results are listed in Table 2.

Applications of thermal analysis on Joypox and Rectivard tablets
Figure 4 A shows the DTA curves of Joypox and Rectivard tablets, the dosage forms of DAP and VAR, respectively.The endothermic and exothermic peaks of DAP and VAR (Figure 1
Figure 2 shows the numbering of DAP and VAR.MO calculation data for DAP reveal that the loss of C 17 H 19 NO in the first step of decomposition is due to the rupture of C13-C14 bond (bond length = 1.536Å and bond order = 0.975), C12-C13 bond (bond length = 1.528Å and bond order = 0.982), C14-C15 bond (bond length = 1.512Å and bond order = 0.967), C14-N21 bond (bond length = 1.507Å and bond order = 0.964), N21-C22 bond (bond length = 1.483Å and bond order = 0.994), N21-C23 bond (bond length = 1.480Å and bond order = 0.992) and O11-C12 bond (bond length = 1.431Å and bond order = 0.950).The loss of C 4 H 4 in the second step is due to the rupture of C3-C4 bond (bond length = 1.422Å and bond order = 1.218) and C5-C6 bond (bond length = 1.421Å and bond order = 1.221).MO calculations of VAR revealed that in the third decomposition step, the losses of SO 2 and C 6 H 13 N 2 are due to the rupture of C1-S24 bond (bond length = 1.786 and Å bond order = 0.712), S24-N27 bond (bond length = 1.772Å and bond order = 0.695), the losses of C 3 H 7 and CH 3 are due to the rupture of C17-C21 bond (bond length = 1.488Å and bond order = 0.971), C19-C20 bond (bond length = 1.473Å and bond order = 0.998), respectively.The rupture of C13-C14 bond (bond length = 1.449Å and bond order = 1.001) and N11-N12 bond (bond length = 1.388Å and bond order = 1.021) causes the loss of C 3 N 2 and C 10 H 7 N 2 O 2 for the fourth and the fifth steps, respectively.

Figure 2 .
Figure 2. Thermal decomposition of patterns, numbering of DAP and VAR.

Figure 3
Figure3shows the DSC curves of DAP and VAR, very strong and sharp endothermic peaks appear at 181.75 °C and 218.93 °C which may be attributed to the melting of DAP and VAR, respectively.

Figure 3 .
Figure 3. DSC curves of DAP and VAR.

Figure 5
Figure5shows the DSC curves of Joypox and Rectivard tablets, weak and sharp endothermic peaks at 144.62 °C and 187.68 °C which may be attributed to melting of DAP and VAR in tablets, respectively.These melting points values are lesser than the listed values of DAP and VAR in Table2.The decreasing in melting points values is due to the presence of excipients.Other broad and weak endothermic peaks appear at 192.21 °C (Joypox tablets), 66.99 °C and 217.24 °C (Rectivard tablets).ConclusionThis paper is the first attempt to study the thermal behavior of DAP and VAR using thermal analysis and
) are different in their values and shapes in comparison with the endothermic and exothermic peaks of Joypox and Rectivard tablets.An endothermic peak appears at 148.25 °C and a broad endothermic peak between 156.61 °C and 280.67 °C in DTA curves of Joypox and Rectivard tablets which may be attributed to the melting their active ingredients, DAP and VAR, respectively.These values are smaller than that of pure drugs 183.57°C and 218.38 °C for DAP and VAR, respectively according to the presence of excipients in tablets which act as impurities and decreasing the melting point of the drugs.Also the strong and sharp exothermic peaks at 553.70 °C and 577.81 °C for DAP and VAR appear as very weak and broad peaks between 390.26 °C and 724.97 °C and between 419.35 °C and 678.89 °C in case of Joypox and Rectivard tablets, respectively.Figure4 Bshows the DTA curves of excipients.The results are listed in Table2.

Table 2 .
Melting point and degree of purity of DAP and VAR and endothermic and exothermic peaks of inactive ingredients.